RU2489432C2 - TRIAZOLO[1,5-a]QUINOLINES AS LIGANDS OF ADENOSINE A3 RECEPTOR - Google Patents

Abstract

FIELD: biotechnologies.

SUBSTANCE: new derivatives of triazolo[1,5-a]quinoline of general formula (I)

, where X means -NH-; R¹³-cyano; R¹ and R² mean H or methyl; R⁵-phenyl, possibly substituted, or 5- or 6-member heterocyclyl; R³ means phenyl or one atom of nitrogen containing 6-member heterocyclyl; R⁴ - one atom of nitrogen containing 6-member heterocyclyl or a group of the formula (a),

, where R⁶ and R⁷ - independently mean C_3-6cycloalkyl or C_1-4alkyl; or a group of the formula (b)

, where R⁸ and R⁹ mean C_1-4alkyl; Z - oxygen or a group -NR¹²-, where R¹² - hydrogen, C_1-4alkyl, C_3-6 cycloalkyl, benzyl, -CH₂-acetyl, -CH₂-CH₂-O-CH₂-CH₃ or acetyl; W means nitrogen atom or a group -CH-; m and o mean 2; p and r mean zero or 1; t means zero; methods of their production, new intermediate compounds of described methods of production, a pharmaceutical composition containing these compounds, and application of compounds of common formula (I) and their pharmaceutical acceptable salts as ligands of adenosine A3 receptor in treatment of different diseases.

EFFECT: improved properties of compounds.

Description

The present invention relates to adenosine receptor ligands. A₃ of the general formula (I), of which it is preferable to antagonists, to their salts, solvates, N-oxides and isomers, to pharmaceutical compositions containing compounds of the general formula (I), their salts, solvates, N-oxides and isomers, to the use of compounds general formula (I), their salts, solvates, N-oxides and isomers, to obtain compounds of general formula (I), their salts, solvates, N-oxides and isomers, as well as new intermediates of general formula (II), ( VI), (XI), (XII) and (XV), and to their receipt.

Adenosine is a known component of several biologically active endogenous molecules (ATP, NAD ⁺ , nucleic acids). In addition, it plays an important regulatory role in many physiological processes. The effect of adenosine on cardiac function was already discovered in 1929 (Drury and Szentgyörgyi, J Physiol 68: 213, 1929). Identification of the increasing number of physiological functions mediated by adenosine and the discovery of new subtypes of adenosine receptors provide opportunities for the therapeutic use of certain ligands (Poulse SA and Quinn RJ Bioorganic and Medicinal Chemistry 6: 619, 1998).

To date, adenosine receptors have been classified into three main classes: A ₁ , A _2, and A ₃ . Subtype A _{1 is} partially responsible for the inhibition of adenylate cyclase by binding to the membrane protein G _i , and partially affects other systems of secondary messengers. The A ₂ receptor subtype can be divided into the following two subtypes - A _2a and A _2b - which stimulate the activity of adenylate cyclase. The adenosine A ₃ receptor sequence has recently been identified from a rat testis cDNA library. Later it was proved that it corresponds to a new functional adenosine receptor. A ₃ receptor activation is also associated with several secondary messenger systems, for example, inhibition of adenylate cyclase and stimulation of phospholipase C and D.

Adenosine receptors are found in several organs and regulate their functions. Like a_one, so A_2a receptors play important roles in the central nervous system and cardiovascular system. In the central nervous system, adenosine inhibits the release of synaptic mediators, and this effect is mediated by receptors A_one. There are also A receptors in the heart._one mediate the negative inotropic, chronotropic and dromotropic effects of adenosine. Adenosine A Receptors_2a, which are localized in a relatively higher amount in the striatum, show a functional interaction with dopamine receptors in the regulation of synaptic conduction. Adenosine Receptors A_2a on endothelial and smooth muscle cells, they are responsible for vasodilatation induced by adenosine (Baraldi P.G. et al. Chem. Rev. 2008, 108, 238-263).

Based on the identification of mRNA, adenosine A _2b receptors are widely distributed in various tissues. They have been identified in almost every type of cell, but their expression is highest in the intestines and bladder. This subtype probably also has an important regulatory function in regulating the tone of smooth muscle cells in blood vessels and plays a role in mast cell function (Volpini R. et al. Curr. Topics in Med. Chem. 2003, 3, 427-443).

The expression levels of A ₃ adenosine receptors are quite low compared to other subtypes and are highly species dependent. Adenosine A ₃ receptors are expressed primarily in the central nervous system, testis, and immune system and appear to be involved in modulating mast cell release by mast cells in an immediate-type hypersensitivity reaction and in the migration of neutrophilic granulocytes (Y. Chen et al., Science 2006, 314: 1792-1795).

For therapeutic use, it is important to ensure that the molecules are selective for other adenosine receptors, therefore they do not bind, or only bind in the case of a very high concentration, with subtypes A ₁ , A _2a and A _2b of adenosine receptors.

The A ₃ antagonists described in the literature to date belong to the groups of flavonoids derived from 1,4-dihydropyridine, thiazolonaphthyridines, thiazolopyrimidines and aminoquinolines. However, many of the antagonists that are effective and selective for subtypes of adenosine are highly oleophilic in nature, therefore, they have insufficient water solubility. This property prevents their use in vivo. As can be seen from the literature, there is an increasing number of studies aimed at obtaining water-soluble adenosine A ₃ receptor antagonists (Ch. E. Mϋller et al., J. Med. Chem. 45: 3440, 2002; A. Maconi et al., J. Med. Chem. 45: 3579, 2002).

Patent application WO 03/053968 describes triazolo-quinoline derivatives, a new structural group of effective A ₃ adenosine antagonists. The compounds of the general formulas (1) and (1a) of patent application WO 03/053968 are high selectivity adenosine A ₃ antagonists.

In patent application WO 03/053968, compounds of the general formulas (1) and (1a) are claimed in which

R ^{1 '} means a hydrogen atom or a straight or branched C _1-4 alkyl;

R ^{2 '} means a hydrogen atom or a straight or branched C _1-4 alkyl;

R ^{3 '} means a hydrogen atom or a straight or branched C _1-4 alkyl, or phenyl, thienyl or furyl, optionally substituted with one or more straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups or a halogen atom or a 5- or 6-membered heteroaromatic ring containing one, two or three nitrogen atoms or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups or halogen atoms;

R ^{6 '} represents a hydrogen atom or a cyano group, aminocarbonyl, C _1-4 alkoxycarbonyl or a carboxyl group;

R ^{7 '} means a hydrogen atom or a straight or branched C _1-4 alkyl, or phenyl, benzyl, thienyl, furyl, optionally substituted with a methylenedioxy group, or one or more straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, hydroxyl groups, trifluoromethyl groups, cyano groups or halogen atoms, or a 5- or 6-membered heteroaromatic ring containing one, two or three nitrogen atoms or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, in the case of n necessity substituted by one or more straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups or halogen atoms,

R ^{8 '} , R ^9' , R ^{10 '} and R ^11' independently represent a hydrogen atom, a straight or branched C _1-4 alkyl, a straight or branched C _1-4 alkoxy, hydroxyl group or a halogen atom; or

R ^{8 '} and R ^11' represent a hydrogen atom, and R ^{9 '} and R ^10' together form a methylenedioxy group;

X is a group —CH ₂ -, a group —NH—, a group —NR ^{8 ′} - or a sulfur atom or an oxygen atom or a sulfo group or a sulfoxy group, wherein R ^{8 ′} is a straight or branched C _1-4 alkyl or C _3-6 cycloalkyl;

n is zero, 1 or 2

and their salts, solvates and optically active isomers and their salts, solvates.

These compounds also have the characteristic disadvantage that they are very poorly soluble in water, sometimes they do not dissolve at all, which complicates their use as medicines.

The inventors aimed to obtain new adenosine A ₃ ligands with the quinoline quinoline skeleton, of which preferably antagonists, which would have a strong antagonistic effect and would be selective for the A ₃ receptor, i.e. inhibit the A ₃ receptor at a much lower concentration compared to receptors A ₁ , A _2a and A _2b . The aim of the inventors was also to ensure stability, bioavailability, metabolism, therapeutic index, toxicity and solubility of new compounds that would allow the development of drugs based on them. The next goal was that the compounds, due to their favorable absorption in the small intestine, can be administered orally.

The inventors have found that the compounds of general formula (I),

- wherein

R ¹ represents a hydrogen atom or straight or branched C _1-4 alkyl;

R ² represents a hydrogen atom or a straight or branched C _1-4 alkyl;

R ³ is a hydrogen atom or a straight or branched C _1-4 alkyl, or C _3-6 cycloalkyl, or

phenyl or thienyl or furyl optionally substituted with one or more, same or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, hydroxyl groups or halogen atoms, or

A 5- or 6-membered heterocyclic ring containing one or two or three nitrogen atoms, or a 5-membered heterocyclic ring containing one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more, the same or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, hydroxyl groups or halogen atoms;

R ⁴ is phenyl, benzyl, thienyl or furyl, optionally substituted with a methylenedioxy group, or one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, hydroxyl groups, trifluoromethyl groups, cyano groups or halogen atoms, or

A 5- or 6-membered heterocyclic ring containing one or two, or three, or four nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, or halogen atoms, or

a group of general formula (a),

- wherein

R⁶ and R⁷ independently represent a hydrogen atom, C_3-6 cycloalkyl or benzyl, or

straight or branched C _1-4 alkyl, optionally substituted by an amino group, an amino group substituted by one or two identical or different straight or branched C _1-4 alkyl groups, a hydroxyl group, a carboxyl group or a straight or branched C _1-4 alkoxy group , or

a group of general formula (b),

- wherein

R ⁸ and R ⁹ independently represent a straight or branched C _1-4 alkyl, C _3-6 cycloalkyl or hydroxyl group;

Z is an oxygen atom, a sulfur atom, a group —CHR ¹¹ - or a group —NR ¹² -, where R ¹¹ and R ¹² independently represent a hydrogen atom, straight or branched C _1-4 alkyl, C _3-6 cycloalkyl, benzyl or —CH ₂ - (straight or branched C _1-5 acyl) -, -CH ₂ -CH ₂ -O- (straight or branched C _1-4 alkyl) - or straight or branched C _1-5 acyl;

W represents a nitrogen atom or a group —CH—;

m is 1, 2 or 3;

o has a value of 1, 2 or 3;

p is zero or 1;

r is zero or 1;

t is zero or 1;

R ⁵ represents a hydrogen atom, a straight or branched C _1-4 alkyl, or

phenyl, benzyl, thienyl or furyl, optionally substituted with a methylenedioxy group or one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, hydroxyl groups, trifluoromethyl groups , cyano groups or halogen atoms, or

A 5- or 6-membered heterocyclic ring containing one or two or three or four nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more identical or different straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, hydroxyl groups or halogen atoms;

R ¹³ represents a cyano group, an aminocarbonyl group, —CO — O— (straight or branched C _1-4 alkyl) or a carboxyl group;

X is a group —CH ₂ -, a group —NH—, a group —NR ¹⁰ - or a sulfur atom, or an oxygen atom, or a group —SO— or —SO ₂ -, where R ¹⁰ is straight or branched C _1-4 alkyl or C _3-6 cycloalkyl;

n is zero, 1 or 2;

and their salts, solvates, N-oxides and isomers, as well as their salts and solvates, meet the criteria defined above, they have better solubility than the known derivatives of triazolo-3-cyanoquinoline, and at the same time they have strong adenosine A ₃ antagonistic effect and selectivity.

In addition, the inventors have found that the compounds of general formula (I) according to the invention exhibit an outstanding anti-inflammatory effect.

Another advantage of the compounds of general formula (I) is that they have very favorable metabolic properties. The triazole ring is stable; undesired aromatic amines were not formed during its metabolism.

Another advantage of the compounds of general formula (I) according to the present invention is that they have advantageous pharmacokinetic properties.

The detailed meanings of the above substituents are as follows:

By a halogen atom is meant a chlorine, fluorine, iodine or bromine atom.

By straight or branched C _1-4 alkyl is meant methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert.-butyl, preferably ethyl or methyl.

By straight or branched C _1-4 alkoxy is meant methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, preferably ethoxy or methoxy.

By C _3-6 cycloalkyl is meant cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

By C _1-5 acyl is meant formyl, acetyl, propionyl, 2-methylpropionyl, butyryl or valeryl.

A 5- or 6-membered heterocyclic ring containing one, two, three or four nitrogen atoms means an aromatic ring or an unsaturated, partially saturated or fully saturated heterocyclic ring, for example pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1 , 2,4-triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, pyrroline, imidazoline, pyrazoline. This ring may be substituted with a C _1-4 alkyl or alkoxy group or a hydroxyl group or a halogen atom.

A heterocycle containing one nitrogen atom and one oxygen atom or one nitrogen atom and one sulfur atom may be an aromatic ring, unsaturated, partially saturated or saturated heterocycle, such as, for example, oxazole, isoxazole, thiazole, isothiazole, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine. This ring may be substituted with a C _1-4 alkyl or alkoxy group or a hydroxyl group or a halogen atom.

Group (b) is preferably a pyrrolidine, piperidino, piperazino, 4-methylpiperazino, 4-acetylpiperazino, 4-acetylmethylpiperazino, 4-ethoxyethylpiperazino, 4-benzylpiperazino, morpholino or a 2,6-dimethylmorphorphino group.

By salts of the compounds of general formula (I) are meant salts obtained with inorganic and organic acids. Preferred salts are those obtained with pharmaceutically acceptable acids, such as, for example, hydrochloric acid, sulfuric acid, ethanesulfonic acid, tartaric acid, malic acid, citric acid, fumaric acid. Salts that are formed during purification or isolation, for example methanesulfonates and tetrafluoroborates, are also included in the scope of the invention.

By solvates is meant solvates obtained with various solvents, such as, for example, water, methyl ethyl ketone or ethanol.

The nitrogen atoms in the triazolo-quinoline ring or, optionally, in the substituents R ³ , R ⁴ or R ⁵ , can be oxidized to N-oxides.

By isomers is meant structural or stereoisomers. Structural isomers can be tautomers in equilibrium, or they can be isolated desmotropes, which are also objects of the invention. The compounds of general formula (I) may contain one or more asymmetric carbon atoms (for example, depending on the values of R ¹ , R ² and R ³ ) and, thus, they can exist in the form of optical isomers, enantiomers or diastereoisomers. These enantiomers and diastereoisomers, as well as mixtures thereof, including racemates, are also objects of the invention.

A narrower group of compounds of general formula (I) is formed by compounds,

- in which

R ¹ represents a hydrogen atom or straight or branched C _1-4 alkyl;

R ² represents a hydrogen atom or a straight or branched C _1-4 alkyl;

R ³ is a hydrogen atom or a straight or branched C _1-4 alkyl, or C _3-6 cycloalkyl, or

phenyl or thienyl or furyl, optionally substituted with one or more, same or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, or halogen atoms, or

A 5- or 6-membered heterocyclic ring containing one or two or three nitrogen atoms, or a 5-membered heterocyclic ring containing one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more, the same or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, or halogen atoms;

R ⁴ is phenyl, benzyl, thienyl or furyl, optionally substituted with a methylenedioxy group or one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, hydroxyl groups , trifluoromethyl groups, cyano groups or halogen atoms, or

A 5- or 6-membered heterocyclic ring containing one or two, or three, or four nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups or halogen atoms, or a group of general formula (a), in which

R⁶ and R⁷ independently represent a hydrogen atom, C_3-6 cycloalkyl, benzyl, or straight or branched C_1-4 alkyl, optionally substituted with an amino group, an amino group substituted with one or two identical or different, straight or branched C_1-4 alkyl groups, hydroxyl groups, carboxyl groups or straight or branched C_1-4 alkoxy groups, or

a group of general formula (b), in which

R ⁸ and R ⁹ independently represent straight or branched C _1-4 alkyl or C _3-6 cycloalkyl;

Z represents an oxygen atom, a sulfur atom, a group —CHR ¹¹ or —NR ¹² , where R ¹¹ and R ¹² independently represent a hydrogen atom, straight or branched C _1-4 alkyl, C _3-6 cycloalkyl, benzyl or —CH ₂ - ( straight or branched C _1-5 acyl) -, -CH ₂ -CH ₂ -O- (straight or branched C _1-4 alkyl) - or straight or branched C _1-5 acyl;

W represents a nitrogen atom or a group —CH—;

m is 1, 2 or 3;

o has a value of 1, 2 or 3;

p is zero or 1;

r is zero or 1;

t is zero or 1;

R ⁵ represents a hydrogen atom, straight or branched C _1-4 alkyl, or phenyl, benzyl, thienyl or furyl, optionally substituted with a methylenedioxy group, or one or more identical or different, straight or branched C _1-4 alkyl groups straight or branched C _1-4 alkoxy groups, hydroxyl groups, trifluoromethyl groups, cyano groups or halogen atoms,

or a 5- or 6-membered heterocyclic ring containing one or two, or three, or four nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups or halogen atoms;

R ¹³ represents a cyano group, aminocarbonyl, a —CO — O— group (straight or branched C _1-4 alkyl) or a carboxyl group;

X is a group —CH ₂ -, a group —NH—, a group —NR ¹⁰ - or a sulfur atom, or an oxygen atom, or a group —SO— or —SO ₂ -, where R ¹⁰ is straight or branched C _1-4 alkyl or C _3-6 cycloalkyl;

n is zero, 1 or 2;

and their salts, solvates, N-oxides and isomers, as well as their salts and solvates.

Another narrower group of compounds of general formula (I) is formed by compounds,

- in which

R ¹ represents a hydrogen atom or straight or branched C _1-4 alkyl;

R ² represents a hydrogen atom or a straight or branched C _1-4 alkyl;

R ³ is phenyl or thienyl, or furyl, optionally substituted with one or more, same or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups or halogen atoms, or

A 5- or 6-membered heterocyclic ring containing three nitrogen atoms, or a 5-membered heterocyclic ring containing one nitrogen atom and one oxygen atom or one nitrogen atom and one sulfur atom, optionally substituted with straight or branched C _1-4 alkyl a group, a straight or branched C _1-4 alkoxy group or a halogen atom;

R ⁴ is phenyl, benzyl, thienyl or furyl, optionally substituted with a methylenedioxy group, or one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, hydroxyl groups, trifluoromethyl groups, cyano groups or halogen atoms, or

A 5- or 6-membered heterocyclic ring containing one or two, or three, or four nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups or halogen atoms, or

a group of general formula (a), in which

R ⁶ and R ⁷ independently represent a hydrogen atom, C _3-6 cycloalkyl or benzyl, or straight or branched C _1-4 alkyl, optionally substituted by an amino group, an amino group substituted by one or two identical or different, straight or branched C _{1- 4} alkyl groups, hydroxyl groups, carboxyl groups or straight or branched C _1-4 alkoxy groups, or

a group of general formula (b), in which

R ⁸ and R ⁹ independently represent straight or branched C _1-4 alkyl or C _3-6 cycloalkyl;

Z represents an oxygen atom, a sulfur atom, a group —CHR ¹¹ or —NR ¹² , where R ¹¹ and R ¹² independently represent a hydrogen atom, straight or branched C _1-4 alkyl, C _3-6 cycloalkyl, benzyl or —CH ₂ - ( straight or branched C _1-5 acyl) -, -CH ₂ -CH ₂ -O- (straight or branched C _1-4 alkyl) - or straight or branched C _1-5 acyl;

W represents a nitrogen atom or a group —CH—;

m is 1, 2 or 3;

o has a value of 1, 2 or 3;

p is zero or 1;

r is zero or 1;

t is zero or 1;

R ⁵ is phenyl, benzyl, thienyl or furyl, optionally substituted with a methylenedioxy group, or one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, hydroxyl groups, trifluoromethyl groups, cyano groups or halogen atoms, or

A 5- or 6-membered heterocyclic ring containing one or two, or three, or four nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups or halogen atoms;

R ¹³ is a cyano group;

X is a group -NH-;

n is zero, 1 or 2;

and their salts, solvates and isomers, and their salts and solvates.

Another narrower group of compounds of general formula (I) is formed by compounds,

- in which

R ¹ represents a hydrogen atom or methyl;

R ² represents a hydrogen atom or methyl;

R ³ is phenyl or thienyl or furyl, optionally substituted with one or more, same or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, or halogen atoms, or

A 5- or 6-membered heterocyclic ring containing one or two or three nitrogen atoms, or a 5-membered heterocyclic ring containing one nitrogen atom and one oxygen atom or one nitrogen atom and one sulfur atom, optionally substituted with one or more, the same or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups or halogen atoms;

R ⁴ is a 6 membered heterocyclic ring containing one nitrogen atom, or

a group of general formula (a), in which

R ⁶ and R ⁷ independently represent straight or branched C _1-4 alkyl, or

a group of general formula (b), in which

R ⁸ and R ⁹ independently represent straight or branched C _1-4 alkyl;

Z is an oxygen atom or a group —NR ¹² -, where R ¹² is a hydrogen atom, straight or branched C _1-4 alkyl, benzyl or acetyl;

W represents a nitrogen atom;

m is 2;

o has a value of 2;

p is zero or 1;

r is zero or 1;

t is zero;

R ⁵ is phenyl, benzyl, thienyl or furyl, optionally substituted with a methylenedioxy group or one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, hydroxyl groups , trifluoromethyl groups, cyano groups or halogen atoms, or

A 5- or 6-membered heterocyclic ring containing one or two, or three, or four nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups or halogen atoms;

R ¹³ is a cyano group;

X is a group -NH-;

n is zero, 1 or 2;

and their salts, solvates, N-oxides and isomers, and their salts and solvates.

Another narrower group of compounds of general formula (I) is formed by compounds,

- in which

R ¹ represents a hydrogen atom or methyl;

R ² represents a hydrogen atom or methyl;

R ³ is phenyl, or a 6-membered heterocyclic ring containing one nitrogen atom;

R ⁴ is phenyl, benzyl, thienyl or furyl, optionally substituted with a methylenedioxy group or one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, hydroxyl groups , trifluoromethyl groups, cyano groups or halogen atoms, or

A 5- or 6-membered heterocyclic ring containing one or two, or three, or four nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups or halogen atoms, or

a group of general formula (a), in which

R ⁶ and R ⁷ independently represent a hydrogen atom, C _3-6 cycloalkyl, benzyl or straight or branched C _1-4 alkyl, optionally substituted by an amino group, an amino group substituted by one or two identical or different, straight or branched C _1-4 alkyl groups, hydroxyl groups, carboxyl groups or straight or branched C _1-4 alkoxy groups, or

a group of general formula (b), in which

R ⁸ and R ⁹ independently represent straight or branched C _1-4 alkyl or C _3-6 cycloalkyl;

Z is an oxygen atom, a sulfur atom, a group —CHR ¹¹ - or a group —NR ¹² -, where R ¹¹ and R ¹² independently represent a hydrogen atom, straight or branched C _1-4 alkyl, C _3-6 cycloalkyl, benzyl or —CH ₂ - (straight or branched C _1-5 acyl) -, -CH ₂ -CH ₂ -O- (straight or branched C _1-4 alkyl) - or straight or branched C _1-5 acyl;

W represents a nitrogen atom or a group —CH—;

m is 1, 2 or 3;

o has a value of 1, 2 or 3;

p is zero or 1;

r is zero or 1;

t is zero or 1;

R ⁵ is phenyl, benzyl, thienyl or furyl, optionally substituted with a methylenedioxy group or one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, hydroxyl groups , trifluoromethyl groups, cyano groups or halogen atoms, or

A 5- or 6-membered heterocyclic ring containing one or two, or three, or four nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups or halogen atoms;

R ¹³ is a cyano group;

X is a group -NH-;

n is zero, 1 or 2;

and their salts, solvates, N-oxides and isomers, and their salts and solvates.

Another narrower group of compounds of general formula (I) is formed by compounds,

- in which

R ¹ represents a hydrogen atom or methyl;

R ² represents a hydrogen atom or methyl;

R ³ is phenyl or thienyl or furyl guppu, optionally substituted with one or more, same or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups or halogen atoms, or

A 5- or 6-membered heterocyclic ring containing one or two or three nitrogen atoms, or a 5-membered heterocyclic ring containing one nitrogen atom and one oxygen atom or one nitrogen atom and one sulfur atom, optionally substituted with one or more identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups or halogen atoms;

R ⁴ is phenyl, benzyl, thienyl or furyl, optionally substituted with a methylenedioxy group or one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, hydroxyl groups , trifluoromethyl groups, cyano groups or halogen atoms, or

A 5- or 6-membered heterocyclic ring containing one or two, or three, or four nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups or halogen atoms, or

a group of general formula (a), in which

R ⁶ and R ⁷ independently represent a hydrogen atom, C _3-6 cycloalkyl, benzyl or straight or branched C _1-4 alkyl, optionally substituted by an amino group, an amino group substituted by one or two identical or different, straight or branched C _1-4 alkyl groups, hydroxyl groups, carboxyl groups or straight or branched C _1-4 alkoxy groups, or

a group of general formula (b), in which

R ⁸ and R ⁹ independently represent straight or branched C _1-4 alkyl or C _3-6 cycloalkyl;

Z is an oxygen atom, a sulfur atom, a group —CHR ¹¹ - or a group —NR ¹² -, where R ¹¹ and R ¹² independently represent a hydrogen atom, straight or branched C _1-4 alkyl, C _3-6 cycloalkyl, benzyl or —CH ₂ - (straight or branched C _1-5 acyl) -, -CH ₂ -CH ₂ -O- (straight or branched C _1-4 alkyl) - or straight or branched C _1-5 acyl;

W represents a nitrogen atom or a group —CH—;

m is 1, 2 or 3;

o has a value of 1, 2 or 3;

p is zero or 1;

r is zero or 1;

t is zero or 1;

R ⁵ is phenyl optionally substituted with a methoxy group, a hydroxyl group or a halogen atom, or

A 5- or 6-membered heterocyclic ring containing one nitrogen atom, or one nitrogen atom and one sulfur atom;

R ¹³ is a cyano group;

X is a group -NH-;

n is zero, 1 or 2;

and their salts, solvates, N-oxides and isomers, and their salts and solvates.

Another narrow group of compounds of general formula (I) is formed by compounds,

- in which

R ¹ represents a hydrogen atom or methyl;

R ² represents a hydrogen atom or methyl;

R ³ is phenyl or thienyl, or furyl, or

A 5- or 6-membered heterocyclic ring containing one or two or three nitrogen atoms, or a 5-membered heterocyclic ring containing one nitrogen atom and one oxygen atom or one nitrogen atom and one sulfur atom;

R ⁴ is a 5- or 6-membered heterocyclic ring containing one or two, or three, or four nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, or

a group of general formula (a), in which

R ⁶ and R ⁷ independently represent a hydrogen atom, C _3-6 cycloalkyl, benzyl, or straight or branched C _1-4 alkyl, or

a group of general formula (b), in which

R ⁸ and R ⁹ independently represent straight or branched C _1-4 alkyl;

Z is an oxygen atom or a group —NR ¹² -, where R ¹² is a hydrogen atom, straight or branched C _1-4 alkyl, C _3-6 cycloalkyl, benzyl or —CH ₂ acetyl, —CH ₂ —CH ₂ —O— CH ₂ —CH ₃ or acetyl;

W represents a nitrogen atom or a group —CH—;

m is 2;

o has a value of 2;

p is zero or 1;

r is zero or 1;

t is zero;

R ⁵ is phenyl, thienyl or furyl, optionally substituted with a methylenedioxy group or one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, hydroxyl groups, trifluoromethyl groups, cyano groups or halogen atoms, or

A 5- or 6-membered heterocyclic ring containing one or two, or three, or four nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom;

R ¹³ is a cyano group;

X is a group -NH-;

n is 1;

and their salts, solvates, N-oxides and isomers, and their salts and solvates.

An even narrower group of compounds of general formula (I) is formed by compounds,

- in which

R ¹ represents a hydrogen atom;

R ² represents a hydrogen atom;

R ³ is phenyl, or

6 membered heterocyclic ring containing one nitrogen atom;

R ⁴ is a 6 membered heterocyclic ring containing one nitrogen atom, or

a group of general formula (b), in which

R ⁸ and R ⁹ are methyl;

Z is an oxygen atom or a group —NR ¹² -, where R ¹² is a hydrogen atom, methyl or acetyl;

W represents a nitrogen atom;

m is 2;

o is 2;

p is zero or 1;

r is zero or 1;

t is zero;

R ⁵ is phenyl optionally substituted with a methoxy group, a hydroxyl group or a halogen atom, or

A 5- or 6-membered heterocyclic ring containing one nitrogen atom, or one nitrogen atom and one sulfur atom;

R ¹³ is a cyano group;

X is a group -NH-;

n is 1;

and their salts, solvates, N-oxides and isomers, and their salts and solvates.

Representative compounds of the general formula (I) are, for example, the following compounds:

2- (3-methoxyphenyl) -7- (morpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline,

2- (4-methoxyphenyl) -7- (morpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline,

2- (4-methoxyphenyl) -7- (2,6-trans-dimethylmorpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline,

2- (pyridin-4-yl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline,

2- (4-methoxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline,

2- (3-methoxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline,

2- (3-hydroxyphenyl) -7- (4-ethylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline,

2- (3-methoxyphenyl) -7- (4-acetylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline,

2- (3-methoxyphenyl) -7- (piperazin-1-yl) -9-bezylamino-10-cyano-s-triazolo [1,5-a] quinoline,

2-phenyl-7- (pyridin-3-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline,

2-phenyl-7- (4-methylpiperazin-1-yl) -9- (2-pyridylmethylamino) -10-cyano-s-triazolo [1,5-a] quinoline,

2- (3-methoxyphenyl) -7- (pyridin-3-yl) -9- (4-pyridylmethylamino) -10-cyano-s-triazolo [1,5-a] quinoline,

and their salts, solvates, N-oxides and isomers, and their salts and solvates.

Representative salts of the compounds of general formula (I) are, for example, the following compounds:

2- (3-methoxyphenyl) -7- (morpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hydrochloride,

2- (4-methoxyphenyl) -7- (morpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hydrochloride,

2- (4-methoxyphenyl) -7- (2,6-dimethylmorpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hydrosulfate,

2- (pyridin-4-yl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline maleate,

2- (4-methoxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hemifumarate monohydrate,

2- (3-methoxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hemifumarate hemihydrate,

2- (3-hydroxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hydrochloride,

2- (3-methoxyphenyl) -7- (4-acetylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hydrosulfate,

2- (3-methoxyphenyl) -7- (piperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline maleate,

2-Phenyl-7- (pyridin-3-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hydrosulfate,

2-phenyl-7- (4-methylpiperazin-1-yl) -9- (2-pyridylmethylamino) -10-cyano-s-triazolo [1,5-a] quinoline hydrochloride,

2- (3-Methoxyphenyl) -7- (pyridin-3-yl) -9- (4-pyridylmethylamino) -10-cyano-s-triazolo [1,5-a] quinoline hydrosulfate.

According to another of its aspects, the present invention also relates to pharmaceutical compositions containing, as active principles, compounds of general formula (I) or their isomers, salts and solvates thereof, which are preferably oral compositions, but compositions for inhalation, parenteral and transdermal administration are also objects of the invention. The above pharmaceutical compositions may be solid or liquid, such as tablets, granules, capsules, plasters, solutions, suspensions or emulsions. Solid compositions, especially tablets and capsules, are preferred pharmaceutical forms.

The above pharmaceutical compositions are prepared using pharmaceutical excipients commonly used in the pharmaceutical industry and conventional manufacturing operations.

The compounds of general formula (I) according to the present invention can be used to treat pathologies where the A ₃ receptor plays a role in the development of the disease.

Compounds that have a selective effect on the A ₃ receptor can be used in the treatment and / or prevention of heart dysfunctions (Y. Guo et al., J Mol. Cell Cardiol. 2001,33: 825-30, RG Black et al. Circ Res. 2002, 91: 165-72), eye, kidney (HT Lee et al. Am J Physiol Regul Integr Comp Physiol. 2006, 291: R959-69), respiratory system, joints (L. Madi J Rheumatol. 2007 34: 20-6) of the gastrointestinal tract (L. Antonioli et al. Infiamm Bowel Dis. 2007 Nov 16, L. Rybaczyk et al. Gastroenterology 2007; 132 (Suppl 2): A-246) and the central nervous system ( GJ Chen et al. J Neurosci Res. 2006, 84: 1848-55). They inhibit mast cell degranulation, inhibit cytokine production, lower intraocular pressure, decrease TNFα release, inhibit the migration and activation of eosinophilic and neutrophilic granulocytes and other inflammatory cells, inhibit smooth muscle contraction of the respiratory tract and inhibit blood plasma infiltration through a blood vessel. By inhibiting the adenosine A ₃ receptor, pathologies that are associated with increased mucin production (e.g., asthma and COPD) can be cured.

Mast cells play a key role in the pathological mechanism of not only allergies, asthma, but also irritable bowel syndrome (IBS). Mast cells transmit stress signals transmitted along the brain-intestine axis and manifested in the release of pro-inflammatory mediators, which can cause excitation of nerve endings, which can affect afferent nerve endings and alter their perception, affect intestinal motility, increase intestinal permeability and, in sensitive individuals, modulate inflammation (World J. Gastroenterol. 2007, 22: 3027-30). A subset of patients with IBS has an increased number of mast cells in the mucous membrane of the colon and colon (Gut 2008, 57: 468-473). In addition, activated mast cells near the nerves of the colon and colon correlate with abdominal pain and visceral allergy in patients with diarrhea in the framework of IBS (Gastroenterology 2004, 126: 693-702, J Gastroenterol Hepatol 2006, 21 (1 Pt l): 71-8). Mast cells are under both paracrine and autocrine regulation of adenosine, in part via the A ₃ mast cell adenosine receptor.

Based on the above effects, A ₃ adenosine receptor antagonists may be therapeutically suitable for use as anti-asthma, anti-ischemic, anti-depressant, anti-arrhythmic, anti-rheumatic, anti-glaucoma, anti-inflammatory drugs for inflammatory and irritable bowel diseases, anti-COPD, anti-kidney drugs , agents for preventing tumors, anti-Parkinsonian drugs and drugs for stimulating cognitive function ktsii. They can also be used in the treatment or prevention of the following diseases: cardiac muscle damage during reperfusion, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), including chronic bronchitis, pulmonary emphysema or shortness of breath, allergic reactions (e.g. , reactions induced by poisonous spitting, urticaria, scleroderma, arthritis), other autoimmune diseases, inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, irritable bowel indroma (IBS), Addison's disease, psoriasis, joint diseases, hypertension, pathological neurological functions, glaucoma and diabetes (Naunyn-Schmiedberg's Arch. Pharmacol. 362: 382, 2000; TiPS 21: 456, 2000, Am. J. Resp Cell Mol. Biol. 35: 549, 2006).

The compounds of the present invention can preferably be used in the treatment of dysfunctions such as asthma (Clin. Exp. Allergy 32: 824, 2002; J. Allergy. Clin. Immuno., 114: 737, 2004), COPD (Am. J. Respir. Crit. Care Med., 173: 398, 2006), RDSV, glaucoma (Investigative Ophthalmology & Visual Science, Vol. 46, 2005), tumor, IBD, IBS (World J. Gastroenterol. 2007, 22: 3027-30), allergic and inflammatory pain (Pain 121: 105, 2006), rheumatoid arthritis (J. Rheumatol. 34: 20-6, 2007), ischemia, hypoxia, cardiac arrhythmias, kidney and mood-related diseases (JPET Fast Forward. Published on April 25, 2007 as DOI: 10.1124 / jpet.107.121665).

According to another of its aspects, the present invention relates to the use of compounds of the general formula (I) in the treatment of the above pathologies. The proposed daily dose is 1-100 mg of the active ingredient, depending on the nature and severity of the disease and on gender, body weight, etc. the patient.

The next object of the invention is to obtain compounds of General formula (I) and intermediate compounds of General formulas (II), (III), (V), (VI), (IX), (X), (XI), (XII), (XIV ) and (XV).

Part of the intermediates of the general formulas (II), (III), (V), (VI), (IX), (X), (XI), (XII), (XIV) and (XV) used in the method according to the invention are new.

Method A) according to the invention is shown in the reaction in scheme 1 (figure 1).

According to Method A) according to the invention, for the preparation of compounds of general formula (I) in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , X and n are as defined above, the 1,2-diamino salt asinium of the general formula (II)

- in which R ¹ , R ² , R ³ , R ⁴ , R ¹³ , X and n are as defined above, and TsO ^- denotes the anion p-toluenesulfonate, is reacted with a compound of the general formula (IV),

wherein

- the value of R ⁵ is as described above, and Y represents a hydrogen atom, a halogen atom or C _1-4 alkoxy, preferably with suitable acid chlorides or esters (DW Robertson, J. Med. Chem., 28, 717, 1985 ), and if desired, the substituents of the compound of general formula (I) are converted into each other by a method known per se , and / or the obtained compound of general formula (I) is converted to its salt, solvate, N-oxide or released from its salt, solvate , and / or are divided into its optically active isomers, or the optically active isomer is converted to racemic connection failed, and if desired, structural isomers are separated.

Aldehydes can also be used to ring closure. Triethylamine in dimethylformamide can preferably be used as the cyclizing agent, but other agents of this type known in organic chemistry can also be used. The cyclization can be carried out at various temperatures, preferably at a temperature of from 20 ° C to 150 ° C.

Method B) according to the invention is shown in the reaction in scheme 2 (figure 2).

According to the invention to obtain compounds of General formula (I), where

R ⁴ is phenyl, benzyl, thienyl or furyl substituted with a methylenedioxy group or one or more, same or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, hydroxyl groups, trifluoromethyl groups , cyano groups or halogen atoms,

or a 5- or 6-membered heterocyclic ring bonded through a carbon atom containing one or two, or three, or four nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted one or more, identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups or halogen atoms, or

a group of the general formula (b), where, if the value t = 1, then W denotes a nitrogen atom or a group —CH—, or, if the value t = 0, then W denotes a group —CH—, and the values Z, m, o , p, r, R ⁸ and R ⁹ are as defined above,

and the values of R ¹ , R ² , R ³ , R ⁵ , R ¹³ , X and n are as defined above,

in method B / 1) a triazole derivative of the general formula (V)

- where E is a halogen atom or trifluoromethanesulfonyl, and the values of R ¹ , R ² , R ³ , R ⁵ , R ¹³ , X and n are as defined above and the compound of general formula (VII),

R ^four -B (OH) ₂

(Vii)

- where the value of R ⁴ is as defined above for method B), is introduced into the reaction under the reaction conditions of Suzuki (A. Kotschy, G. Timari ,: Heterocycles from Transition Metal Catalysis. Springer, 2005), or

in method B / 2) a trialkyltin-triazole derivative of the general formula (VI)

- where R ¹⁴ denotes a straight or branched C _1-4 alkyl, and the values of R ¹ , R ² , R ³ R ⁵ R ¹³ , X and n are as defined above, and the compound of General formula (VIII)

R ^four -E (VIII)

where E is a halogen atom or trifluoromethanesulfonyl and the value of R ⁴ is as defined above for method B), is reacted under the conditions of the Stille reaction (A. Kotschy, G. Timari ,: Heterocycles from Transition Metal Catalysis. Springer, 2005); and if desired, the substituents of the compound of general formula (I) are converted into each other by a method known per se and / or the obtained compound of general formula (I) is converted to its salt, solvate, N-oxide or liberated from its salt, solvate, and / or the optically active isomers are separated into its isomers, or the optically active isomer is converted to a racemic compound, and if desired, the structural isomers are separated.

Method C) according to the invention is shown in the reaction in scheme 3 (figure 3).

According to method C) according to the invention, to obtain compounds of General formula (I), where the values of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , X and n are as defined above, a triazole derivative of General formula (Xii)

- where the values of R ⁴ , R ⁵ and R ¹³ are as defined above, and the compound of General formula (XIII)

- where the values of X, R ¹ , R ² and R ³ and n are as defined above, are introduced into the reaction by a method known per se (Nan Zhang, Bioorg. and Med. Chem. Lett., 10, 2825, 2000) and if desired, the substituents of the compound of general formula (I) are converted to each other by a method known per se and / or the obtained compound of general formula (I) is converted to its salt, solvate, N-oxide or liberated from its salt, solvate, and / or the optically active isomers are separated into its isomers, or the optically active isomer is converted to a racemic compound, and if desired, the structural isomers are separated.

Method D) according to the invention is shown in the reaction in scheme 4 (figure 4). According to method D) of the invention, for the preparation of compounds of general formula (I), wherein the values of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , X and n are as defined above, it is also possible to use the compound of General formula (XV),

- where are the values X, R^one, R², R³, R^four, R⁵, R¹³ and n are as defined above, and TsO^- denotes a p-toluenesulfonate anion which is cyclized in the presence of an organic or inorganic base, preferably triethylamine or pyridine, and if desired, the substituents of the compound of general formula (I) are converted into each other by a method knownper seand / or the obtained compound of general formula (I) is converted into its salt, solvate, N-oxide or released from its salt, solvate, and / or separated into its optically active isomers, or the optically active isomer is converted into a racemic compound, and if structurally isomers are preferably separated.

The starting materials used in the above methods and their preparation are demonstrated as follows.

Compounds of General Formula (II)

where the values of R ¹ , R ² , R ³ , R ⁴ , R ¹³ and n are as defined above, and TsO ^- denotes the p-toluenesulfonate anion, are new materials, and they can be obtained by several known methods, among others, for example, as shown in the reaction in scheme 1 (figure 1), from a compound of general formula (III)

- where the values of X, R ¹ , R ² , R ³ , R ⁴ , R ¹³ and n are as defined above, the N-amination reaction known in organic chemistry (EE Glover, RT Rowbotton, J. Chem. Soc. Perkin Trans L, 376, 1976; G. Timari, Gy. Hajόs, S. Batori and A. Messmer, Chem. Ber., 125, 929, 1992). Regarding the N-aminating agent, O-tosylhydroxylamine (TSH) is preferably used, but other known compounds can also be used as N-aminating agents.

The compounds of general formula (III) are partially known from patent application WO 2005/009969, or they can be obtained by analogy with the method described there.

Compounds of General formula (III), in which

R ⁴ is phenyl, benzyl, thienyl or furyl substituted with a methylenedioxy group or one or more, same or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, hydroxyl groups, trifluoromethyl groups , cyano groups or halogen atoms, or

A 5- or 6-membered heterocyclic ring bonded through a carbon atom containing one or two, or three, or four nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more, the same or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups or halogen atoms, or

a group of the general formula (b), where,

if the value t = 1, then W denotes a nitrogen atom or a group —CH—, or if the value t = 0, W denotes a group —CH—, and the values Z, m, o, p, r, R ⁸ and R ⁹ are such as defined above

and the values of R ¹ , R ² , R ³ , R ⁵ , R ¹³ , X and n are as defined above,

can be obtained analogously to the version of method B / 1) according to the invention using 6-halogen-aminoquinoline derivatives known from patent application WO 02/096879, or their analogues as starting material.

Compounds of General Formula (V)

- where E is a halogen atom and the values of R ¹ , R ² , R ³ , R ⁵ , R ¹³ , X and n are as defined above, are partially known from international patent application WO 03/053968 or can be obtained by analogy with the method described there.

Compounds of general formula (V), wherein E is trifluoromethanesulfonyl and the meanings of R ¹ , R ² , R ³ , R ⁵ , R ¹³ , X and n are as defined above, can be obtained from the corresponding compounds described in the international application patent WO 03/053968 or from their analogues containing a hydroxyl group for group E, by a method known in organic chemistry (G. Timari, T. Soόs, Gy. Hajόs, A. Messmer, J. Nacsa and J. Molnar, Bioorg Med. Chem. Lett, 2831, 1996).

Compounds of General Formula (VI)

- where R ¹⁴ denotes straight or branched C _1-4 alkyl and the values of R ¹ , R ² , R ³ , R ⁵ , R ¹³ , X and n are as defined above, are new compounds. Intermediates of general formula (VI) can be prepared by several known methods, for example, according to reaction scheme 2 (FIG. 2), from a compound of general formula (V) by methods known in organic chemistry (A. Kotschy, G. Timari: Heterocycles from Transition Metal Catalysis. Springer, 2005, WO 2006/051341). Hexamethyldannate is preferably used to prepare the trialkyl stannate group.

Compounds of General Formula (XII)

- where the values of R ⁴ , R ⁵ and R ¹³ are as defined above, are new compounds. Compounds of general formula (XII), wherein R ⁴ , R ^3, and R ¹³ are as defined above, can be prepared from a compound of general formula (XI)

- where the values of R ⁴ , R ⁵ and R ¹³ are as defined above, by methods known per se (DL Leysen, J. Heterocyclic Chem., 24, 1611, 1987), according to reaction scheme 3 (figure 3).

Compounds of general formula (XI) - wherein R ⁴ , R ^5, and R ¹³ are as defined above - are new compounds. To obtain them, the salt of 1,2-diamino-azinium of General formula (X)

- where the values of R ⁴ and R ¹³ are as defined above, and TsO ^- denotes a p-toluenesulfonate anion - is reacted with a compound of the general formula (IV)

- where the values of R ⁵ are as defined above, and Y represents a hydrogen atom, a halogen atom or a C _1-4 alkoxy group, preferably with suitable acid chlorides or esters (DW Robertson, J. Med. Chem., 28, 717, 1985). Aldehydes can also be used to ring closure.

Triethylamine in dimethylformamide is preferably used as the cyclizing agent, but other agents of this type known in organic chemistry can also be used. The cyclization can be carried out at various temperatures, preferably at 20 ° C-150 ° C.

Compounds of general formula (X) - where the values of R ⁴ and R ¹³ are as defined above - are new compounds, they can be obtained by several known methods, for example, according to reaction scheme 3 (figure 3), from a compound of general formula (IX ),

- where the values of R ⁴ and R ¹³ are as defined above, the N-amination reaction known in organic chemistry (EE Glover, RT Rowbotton, J. Chem. Soc. Perkin Trans L, 376, 1976, G. Timari, Gy Hajόs, S. Batori and A. Messmer, Chem. Ber., 125, 929, 1992). Regarding the N-amination agent, O-tosyl hydroxylamine (TSH) is preferably used, but other known compounds can also be used as N-amination agents.

The compounds of general formula (IX) are partially known from international patent application WO 2005/009969 or can be obtained by analogy with the method described in international patent application WO 2005/009969, starting from 2-nitrobenzoic acid containing the corresponding substituent R ⁴ in position 5.

Compounds of General Formula (XV)

- where X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ and n are as defined above, and TsO ^- denotes the p-toluenesulfonate anion - are new compounds. Intermediates of general formula (XV) can be prepared by several known methods, for example, according to reaction scheme 4 (figure 4), from a compound of general formula (XIV),

- where the values of X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ and n are as defined above, the N-amination reaction known in organic chemistry (EE Glover, RT Rowbotton, J. Chem Soc. Perkin Trans L, 376, 1976, G. Timari, Gy. Hajόs, S. Batori and A. Messmer, Chem. Ber., 125, 929, 1992). O-tosyl hydroxylamine (TSH) is preferably used as the N-amination agent, but other known compounds can also be used as N-amination agents.

Compounds of general formula (XIV) are partially known from international patent application WO 2005/009969 or can be obtained by analogy to the method described in patent application WO 2005/009969 from compounds of general formula (III).

General procedure for producing N-oxides:

The corresponding amine was dissolved in chloroform, and excess mCPBA was added in portions. After stirring at ambient temperature for 5 hours, the reaction mixture was extracted with 10% sodium carbonate solution, and the organic layer was evaporated. The solid residue was purified by chromatography to give the desired N-oxides.

General procedure for obtaining salts:

To a solution of a suitable base dissolved in tetrahydrofuran was added a solution of 1.2 equivalents of acid (hydrochloric acid, sulfuric acid, fumaric acid, maleic acid) in ethanol and stirred at ambient temperature. The resulting precipitate was filtered and washed with cold ethanol to give the desired salts.

Compounds according to the invention of the general formulas (I) (II), (III), (V), (VI), (IX), (X), (XI), (XII), (XIV) and (XV), their preparation and the biological activity of the compounds of general formula (I) are shown in the examples below, which do not limit the claims.

EXAMPLES

EXAMPLE 1

2- (3-methoxyphenyl) -7- (morpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline

In the general formula (I), R ¹ and R ² are a hydrogen atom, R ³ is phenyl, R ⁵ is 3-methoxyphenyl, R ⁴ is a group (b) where W is a nitrogen atom, Z is an oxygen atom, m and o are 2, r, p and t are 0, R ¹³ is a cyano group, X is an NH group, and n is 1.

a) 1,2-diamino-3-cyano-4-benzylamino-6- (morpholin-4-yl) quinolinium tosylate:

To a solution of 3 g of 2-amino-3-cyano-4-benzylamino-6-morpholino-quinoline in 20 ml of dimethylformamide, 2.2 g of O-tosylhydroxylamine dissolved in 25 ml of dichloromethane was added dropwise at 20 ° C in 15 minutes . After 5 hours of stirring, the precipitated crystalline material was filtered. After drying, 3.8 g of the target compound were obtained (MH ⁺ : 376).

b) 2- (3-methoxyphenyl) -7- (morpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline:

3.5 g of 1,2-diamino-3-cyano-4-benzylamino-6- (morpholin-4-yl) quinolinium tosylate was dissolved in 50 ml of ethanol and 12 ml of 1 mol / liter sodium ethoxide was added to the solution in an ethanol solution and 2 g of 3-methoxybenzaldehyde. The reaction mixture was heated at the boiling point of the solvent for 4 hours. The precipitated crystalline material was filtered and recrystallized from dimethylformamide. After drying, 1.8 g of the target compound was obtained (MH ⁺ : 491).

¹ H-NMR (DMSO-d ₆ ), δ, ppm: 8.68 (broad s, 1H); 8.23 (d, 1H); 7.79-7.64 (m, 4H); 7.43-7.05 (m, 7H); 5.15 (d, 2H); 3.84 (s, 3H); 3.80-3.78 (m, 4H); 3.32-3.30 (m, 4H).

EXAMPLE 1.2

2- (3-methoxyphenyl) -7- (morpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hydrochloride

To a solution of 0.4 g of 2- (3-methoxyphenyl) -7- (morpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline in 30 ml of ethyl acetate was added 5 ml 4 mol / liter hydrogen chloride in solution in ether. The precipitated crystalline material was filtered. After drying, 0.42 g of the target compound was obtained (MH ⁺ : 491).

¹ H-NMR (DMSO-d ₆ ), δ, ppm: 8.68 (broad s, 1H); 8.23 (d, 1H); 7.82-7.64 (m, 4H); 7.43-7.05 (m, 7H); 5.15 (d, 2H); 3.84 (s, 3H); 3.82-3.78 (m, 4H); 3.43-3.30 (m, 4H)

EXAMPLE 2

2- (4-methoxyphenyl) -7- (morpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline

In the general formula (I), R ¹ and R ² are a hydrogen atom, R ³ is phenyl, R ⁵ is 4-methoxyphenyl, R ⁴ is a group (b) where W is a nitrogen atom, Z is an oxygen atom, m and o are 2, r, p and t are 0, R ¹³ is a cyano group, X is an NH group, and n is 1.

a) 2- (4-methoxyphenyl) -7- (morpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline:

To a solution of 3.5 g of 1,2-diamino-3-cyano-4-benzylamino-6- (morpholin-4-yl) quinolinium tosylate described in Example 1, 12 ml of sodium ethoxide in a concentration of 1 mol was added in 50 ml of ethanol / liter in ethanol solution and 2 g of 4-methoxybenzaldehyde. The reaction mixture was heated at the boiling point of the solvent for 4 hours. The precipitated crystalline material was filtered and recrystallized from dimethylformamide. After drying, 1.65 g of the target compound was obtained (MH ⁺ : 491).

^oneH-NMR (DMSO-d₆), δ, ppm: 8.72 (broad, 1H); 8.23 (d, 1H); 7.79-7.64 (m, 4H); 7.43-7.05 (m, 7H); 5.13 (d, 2H); 3.94 (s, 3H); 3.80-3.78 (m, 4H); 3.32-3.30 (m, 4H).

EXAMPLE 2.2

2- (4-methoxyphenyl) -7- (morpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hydrochloride

The target compound was prepared by the general method disclosed above by adding a hydrochloric acid solution to the compound obtained according to Example 2.

¹ H-NMR (DMSO-d ₆ ), δ, ppm: 8.81 (broad s, 1H); 8.33 (d, 1H); 7.82-7.64 (m, 4H); 7.43-7.05 (m, 7H); 5.15 (d, 2H); 3.96 (s, 3H); 3.80-3.78 (m, 4H); 3.36-3.32 (m, 4H).

EXAMPLE 3

2- (4-methoxyphenyl) -7- (2,6-dimethylmorpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline

In the general formula (I), R ¹ and R ² are a hydrogen atom, R ³ is phenyl, R ⁵ is 4-methoxyphenyl, R ⁴ is a group (b) where W is a nitrogen atom, Z is an oxygen atom, m and o are 2, r and p are 1, R ⁸ and R ⁹ are methyl, t = 0, R ¹³ is a cyano group, X is an NH group, and n = 1.

a) 2-nitro-5- (2,6-dimethylmorpholin-4-yl) benzoic acid

A mixture of 5 g of 2-nitro-5-chlorobenzoic acid and 15 ml of 2,6-dimethylmorpholine was stirred at 120 ° C for 6 hours. 150 ml of ethyl acetate was added to the reaction mixture. The precipitated yellow crystalline material was filtered, dissolved in 15 ml of water. The mixture was adjusted to pH 6 with acetic acid. The precipitated material was filtered, washed with water and dried, yielding 4.2 g of the target compound (MH ⁺ : 281).

b) 2-amino-5- (2,6-dimethylmorpholin-4-yl) benzoic acid:

A mixture of 6 g of 2-nitro-5- (2,6-dimethylmorpholin-4-yl) benzoic acid, 15 ml of cyclohexene and 3 g of Pd / C (10%) was heated under reflux for 6 hours. The hot reaction mixture was filtered through a pad of celite. After evaporation of the filtrate, 4.8 g of the expected product are obtained (MH ⁺ : 251).

c) 5- (2,6-dimethylmorpholin-4-yl) isatoic acid anhydride:

To a mixture of 8.9 g of 2-amino-5- (2,6-dimethylmorpholin-4-yl) benzoic acid in 60 ml of dioxane, 10 ml of diphosgene were added dropwise with stirring and external cooling with cold water. The mixture was heated under reflux for 4 hours. Solid material was filtered from a cold reaction mixture, washed with 50 ml of ether. The product was stirred for 5 minutes in a mixture of 50 ml of methanol and 5 ml of triethylamine, then it was filtered off and washed with 30 ml of methanol. After drying, 7 g of the expected product is obtained (MH ⁺ : 277).

d) 2-amino-3-cyano-4-hydroxy-6- (2,6-dimethylmorpholin-4-yl) quinoline:

4 g of malonitrile was dissolved in 50 ml of dimethylformamide. To the solution, in several parts, was added 2.4 g of a 60% dispersion of sodium hydride in oil. 8 g of 5- (2,6-dimethylmorpholin-4-yl) isatoic acid anhydride was added to the clear solution, and the mixture was stirred at ambient temperature for 10 hours. The reaction mixture was diluted with 70 ml of water and extracted with 2 × 30 ml of ethyl acetate. The aqueous phase was evaporated in vacuo, the solid residue was dissolved in 20 ml of water and adjusted to pH 6. The precipitated material was filtered, washed with water. After drying, 6.5 g of the target compound are obtained (MH ⁺ : 299).

e) 2-amino-3-cyano-4-chloro-6- (2,6-dimethylmorpholin-4-yl) quinoline:

A mixture of 1.7 g of 2-amino-3-cyano-4-hydroxy-6- (2,6-dimethylmorpholin-4-yl) quinoline and 3.4 ml of phosphoryl chloride was stirred at 120 ° C. for 4 hours. The cooled reaction mixture was poured onto 30 g of ice, the pH of the mixture was adjusted to 8 using a 10% sodium hydroxide solution, and the precipitated material was filtered. After drying, 1.5 g of the target compound was obtained (MH ⁺ : 317).

f) 2-amino-3-cyano-4-benzylamino-6- (2,6-dimethylmorpholin-4-yl) quinoline:

3 g of 2-amino-3-cyano-4-chloro-6- (2,6-dimethylmorpholin-4-yl) quinoline and 6 ml of benzylamine were stirred at 125 ° C for 3 hours. The reaction mixture was poured into 30 ml of water. The precipitated material was filtered, washed with 20 ml of water. After drying, 2.3 g of the target compound are obtained (MH ⁺ : 388).

g) 1,2-diamino-3-cyano-4-benzylamino-6- (2,6-dimethylmorpholin-4-yl) quinolinium tosylate:

To a solution of 3.2 g of 2-amino-3-cyano-4-benzylamino-6- (2,6-dimethylmorpholin-4-yl) quinoline in 20 ml of dimethylformamide was added dropwise 2.2 g of O-tosylhydroxylamine in 25 ml of dichloromethane at 20 ° C in 15 minutes. After 5 hours of stirring, the precipitated crystalline material was filtered. After drying, 3.4 g of the target compound was obtained (MH ⁺ : 403).

h) 2- (4-methoxyphenyl) -7- (2,6-dimethylmorpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline:

3.5 g of 1,2-diamino-3-cyano-4-benzylamino-6- (2,6-dimethylmorpholin-4-yl) quinolinium tosylate was dissolved in 50 ml of ethanol and 12 ml of 1 mol of sodium ethoxide was added to this solution. / liter in ethanol solution and 2 g of 4-methoxybenzaldehyde. The reaction mixture was heated at the boiling point of the solvent for 4 hours. The precipitated crystalline material was filtered and recrystallized from dimethylformamide. After drying, 1.85 g of the target compound was obtained (MH ⁺ : 518).

^oneH-NMR (DMSO-d₆), δ, ppm: 8.70 (broad, 1H); 8.26 (d, 1H); 7.89-7.64 (m, 4H); 7.43-7.15 (m, 7H); 5.16 (d, 2H); 3.90 (s, 3H); 3.77-3.74 (m, 4H); 2.41-2.38 (m, 2H); 1.2 (d, 6H).

EXAMPLE 3.2

2- (4-methoxyphenyl) -7- (2,6-dimethylmorpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hydrosulfate:

The target compound was obtained by the general method described above by adding a solution of sulfuric acid to the compound obtained according to Example 3.

^oneH-NMR (DMSO-d₆), δ, ppm: 8.70 (broad, 1H); 8.42 (d, 1H); 7.91-7.64 (m, 4H); 7.53-7.25 (m, 7H); 5.26 (d, 2H); 3.92 (s, 3H); 3.97-3.76 (m, 4H); 2.51-2.48 (m, 2H); 1.25 (d, 6H).

EXAMPLE 4

2- (Pyridin-4-yl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline

In the general formula (I), R ¹ and R ² are a hydrogen atom, R ³ is phenyl, R ⁵ is pyridin-4-yl, R ⁴ is a group (b) where W is a nitrogen atom, Z is a group —NR ¹² - where R ¹² is methyl, m and o are 2, r, p and t are 0, R ¹³ is a cyano group, X is an NH group and n = 1.

a) 1,2-diamino-3-cyano-4-benzylamino-6- (4-amino-4-methylpiperazin-4-yl-1-yl) quinolinium ditosylate.

To a solution of 3.7 g of 2-amino-3-cyano-4-benzylamino-6- (4-methylpiperazin-1-yl) quinoline in 20 ml of dimethylformamide was added dropwise at 20 ° C. over 15 minutes, 4.4 g of O- tosylhydroxylamine in 50 ml of dichloromethane. After 5 hours of stirring, the precipitated crystalline material was filtered. After drying, 3.3 g of the target compound are obtained (MH ⁺ : 404).

b) 2- (pyridin-4-yl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline:

3.2 g of 1,2-diamino-3-cyano-4-benzylamino-6- (4-amino-4-methylpiperazin-4-yl-1-yl) quinolinium ditosylate was dissolved in 50 ml of ethanol, and to this solution was added 20 ml of sodium ethoxide with a concentration of 1 mol / liter in ethanol solution and 2.1 g of pyridine-4-carbaldehyde. The reaction mixture was heated at the boiling point of the solvent for 4 hours. The precipitated crystalline material was filtered and recrystallized from dimethylformamide. After drying, 1.15 g of the target compound was obtained (MH ⁺ : 474).

^oneH-NMR (DMSO-d₆), δ, ppm: 8.77 (broad s, 1H); 8.23 (d, 1H); 8.12-7.64 (m, 6H); 7.43-7.05 (m, 5H); 5.13 (d, 2H); 3.86 (s, 3H); 3.46-3.34 (m, 4H); 2.53-2.46 (m, 4H); 2.28 (s, 3H).

EXAMPLE 4.2

2- (pyridin-4-yl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline maleate:

The target compound was prepared by the general method disclosed above by adding maleic acid solution to the compound obtained according to Example 4.

^oneH-NMR (DMSO-d₆), δ, ppm: 8.78 (broad, 1H); 8.24 (d, 1H); 8.12-7.64 (m, 6H); 7.43-7.05 (m, 5H); 6.3 (s, 2H); 5.15 (d, 2H); 3.86 (s, 3H); 3.46-3.34 (m, 4H); 2.51-2.46 (m, 4H); 2.31 (s, 3H).

EXAMPLE 5

2- (4-methoxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline

In the general formula (I), R ¹ and R ² are a hydrogen atom, R ³ is phenyl, R ⁵ is 4-methoxyphenyl, R ⁴ is a group (b) where W is a nitrogen atom, Z is a group —NR ¹² -, where R ¹² is methyl, m and o are 2, r, p and t are 0, R ¹³ is a cyano group, X is an NH group, and n = 1.

a) 2- (4-methoxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline:

3.2 g of 1,2-diamino-3-cyano-4-benzylamino-6- (4-amino-4-methylpiperazin-4-yl-1-yl) quinolinium ditosylate obtained according to Example 4 was dissolved in 50 ml of ethanol and to this solution was added 20 ml of sodium ethoxide with a concentration of 1 mol / liter in ethanol solution and 2 g of 4-methoxybenzaldehyde. The reaction mixture was heated at the boiling point of the solvent for 4 hours. The precipitated crystalline material was filtered and recrystallized from dimethylformamide. After drying, 1.1 g of the target compound was obtained (MH ⁺ : 504).

¹ H-NMR (DMSO-d ₆ ), δ, ppm: 8.65 (broad s, 1H); 8.21 (d, 1H); 7.77-7.64 (m, 4H); 7.43-7.05 (m, 7H); 5.12 (d, 2H); 3.81 (s, 3H); 3.36-3.34 (m, 4H); 2.53-2.49 (m, 4H); 2.26 (s, 3H).

EXAMPLE 5.2

2- (4-methoxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hemifumarate monohydrate:

The target compound was obtained by the general method described above by adding a solution of fumaric acid to the compound obtained according to Example 5.

¹ H-NMR (DMSO-d ₆ ), δ, ppm: 8.68 (broad s, 1H); 8.23 (d, 1H); 7.81-7.64 (m, 4H); 7.53-7.05 (m, 7H); 6.75 (s, 1H); 5.14 (d, 2H); 3.84 (s, 3H); 3.36-3.34 (m, 4H); 2.53-2.49 (m, 4H); 2.33 (s, 3H).

EXAMPLE 6

2- (3-methoxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline

In the general formula (I), R ¹ and R ² are a hydrogen atom, R ³ is phenyl, R ⁵ is 3-methoxyphenyl, R ⁴ is a group (b) where W is a nitrogen atom, Z is a group —NR ¹² -, where R ¹² is methyl, m and o are 2, r, p and t are 0, R ¹³ is a cyano group, X is an NH group, and n = 1.

a.) 2- (3-methoxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline:

3.3 g of 1,2-diamino-3-cyano-4-benzylamino-6- (4-amino-4-methylpiperazin-4-yl-1-yl) quinolinium ditosylate obtained according to Example 4 was dissolved in 50 ml of ethanol and to this solution was added 20 ml of 1 mol / liter sodium ethoxide in ethanol solution and 2.1 g of 3-methoxybenzaldehyde. The reaction mixture was heated at the boiling point of the solvent for 4 hours. The precipitated crystalline material was filtered and recrystallized from dimethylformamide. After drying, 1.15 g of the target compound was obtained (MH ⁺ : 504).

^oneH-NMR (DMSO-d₆), δ, ppm: 8.68 (broad, 1H); 8.23 (d, 1H); 7.79-7.64 (m, 4H); 7.43-7.05 (m, 7H); 5.12 (d, 2H); 3.84 (s, 3H); 3.36-3.34 (m, 4H); 2.53-2.49 (m, 4H); 2.26 (s, 3H).

EXAMPLE 6.2

2- (3-methoxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hemifumarate hemihydrate:

The target compound was obtained by the general method described above by adding a solution of fumaric acid to the compound obtained according to Example 6.

^oneH-NMR (DMSO-d₆), δ, ppm: 8.68 (broad, 1H); 8.23 (d, 1H); 7.79-7.64 (m, 4H); 7.43-7.05 (m, 7H); 6.75 (s, 1H); 5.12 (d, 2H); 3.84 (s, 3H); 3.36-3.34 (m, 4H); 2.53-2.49 (m, 4H); 2.31 (s, 3H).

EXAMPLE 7

2- (3-hydroxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline

In the general formula (I), R ¹ and R ² are a hydrogen atom, R ³ is phenyl, R ⁵ is 3-hydroxyphenyl, R ⁴ is a group (b) where W is a nitrogen atom, Z is a group —NR ¹² -, where R ¹² is methyl, m and o are 2, r, p and t are 0, R ¹³ is a cyano group, X is an NH group, and n = 1.

a.) 2- (3-hydroxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline:

3.1 g of 1,2-diamino-3-cyano-4-benzylamino-6- (4-amino-4-methylpiperazin-4-yl-1-yl) quinolinium ditosylate obtained according to Example 4 was dissolved in 50 ml of ethanol and to this solution was added 20 ml of sodium ethoxide with a concentration of 1 mol / liter in ethanol solution and 2 g of 3-hydroxybenzaldehyde. The reaction mixture was heated at the boiling point of the solvent for 4 hours. The precipitated crystalline material was filtered and recrystallized from dimethylformamide. After drying, 1.05 g of the target compound was obtained (MH ⁺ : 490).

¹ H-NMR (DMSO-d ₆ ), δ, ppm: 9.61 (s, 1H); 8.68 (broad. 1H); 8.23 (d, 1H); 7.79-7.64 (m, 4H); 7.43-7.05 (m, 7H); 5.12 (d, 2H); 3.36-3.34 (m, 4H); 2.53-2.49 (m, 4H); 2.26 (s, 3H).

EXAMPLE 7.2

2- (3-hydroxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hydrochloride

The target compound was prepared by the general method disclosed above by adding a hydrochloric acid solution to the compound obtained according to Example 7.

^oneH-NMR (DMSO-d₆), δ, ppm: 9.61 (s, 1H); 8.78 (broad. 1H); 8.26 (d, 1H); 7.81-7.64 (m, 4H); 7.48-7.05 (m, 7H); 5.16 (d, 2H); 3.46-3.34 (m, 4H); 2.55-2.49 (m, 4H); 2.36 (s, 3H).

EXAMPLE 8

2- (3-Methoxyphenyl) -7- (4-acetylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline

In the general formula (I), R ¹ and R ² are a hydrogen atom, R ³ is phenyl, R ⁵ is 3-methoxyphenyl, R ⁴ is a group (b) where W is a nitrogen atom, Z is a group —NR ¹² -, where R ¹² is an acetyl group, m and o are 2, r, p and t are 0, R ¹³ is a cyano group, X is an NH group, and n is 1.

a) 2-nitro-5- (piperazin-1-yl) benzoic acid:

To a suspension of 50 g of 2-nitro-5-chlorobenzoic acid in 750 ml of water, 86 g of piperazine was added and the reaction mixture was heated at the boiling point of the solvent for 20 hours. The mixture was then neutralized with concentrated hydrochloric acid and the precipitated crystalline material was filtered and dried, yielding 62 g of the target compound (MH ⁺ : 252).

b) 2-nitro-5- (4-acetylpiperazin-1-yl) benzoic acid:

30 g of 2-nitro-5- (piperazin-1-yl) benzoic acid was added to 250 ml of acetic anhydride and the mixture was stirred at 100 ° C for 1 hour. The reaction mixture was diluted with 350 ml of ice water, the precipitated crystalline material was filtered and dried, yielding 29 g of the target compound (MH ⁺ : 294).

c) 2-amino-5- (4-acetylpiperazin-1-yl) benzoic acid:

A mixture of 7 g of 2-nitro-5- (4-acetylpiperazin-1-yl) benzoic acid, 15 ml of cyclohexene and 3 g of Pd / C (10%) was heated in 120 ml of ethanol at the boiling point of the solvent for 6 hours. The reaction mixture was filtered by hot filtration through a pad of celite, the filtrate was evaporated, yielding 46.4 g of the target compound (MH ⁺ : 264).

d) 5- (4-acetylpiperazin-1-yl) isatoic acid anhydride:

To a mixture of 18 g of 2-amino-5- (4-acetylpiperazin-1-yl) benzoic acid and 60 ml of dioxane, 10 ml of diphosgene were added dropwise with stirring and cooling with cold water. The mixture was then heated at the boiling point of the solvent for 2 hours. After cooling, the solid material was filtered, washed with 50 ml of ether and dried. Received 24 g of the target compound (MH ⁺ : 290).

e) 2-amino-3-cyano-4-hydroxy-6- (4-acetylpiperazin-1-yl) quinoline:

4 g of malonitrile was dissolved in 50 ml of dimethylformamide, and 2.4 g of a 60% sodium hydride dispersion was added in several parts. 8 g of 5- (4-acetylpiperazin-1-yl) isatoic acid anhydride was added to the clear solution, and the mixture was stirred at ambient temperature for 10 hours. The reaction mixture was diluted with 70 ml of water and extracted with 2 × 30 ml of ethyl acetate. The aqueous phase was evaporated to dryness under reduced pressure, the solid residue was dissolved in 20 ml of water, and pH 6 was adjusted with acetic acid. The precipitated material was filtered and washed with water. After drying, 6.5 g of the target compound are obtained (MH ⁺ : 312).

f) 2-amino-3-cyano-4-chloro-6- (4-acetylpiperazin-1-yl) quinoline:

A mixture of 1.7 g of 2-amino-3-cyano-4-hydroxy-6- (4-acetylpiperazin-1-yl) quinoline, 50 ml of acetonitrile and 3.4 ml of phosphoryl chloride was heated at the boiling point of the solvent for 4 hours. The cooled reaction mixture was poured onto 30 g of ice, the mixture was adjusted to pH 8 using a 10% sodium hydroxide solution, and the resulting precipitate was filtered. After drying, 1.5 g of the target compound was obtained (MH ⁺ : 330).

g) 2-amino-3-cyano-4-benzylamino-6- (4-acetylpiperazin-1-yl) quinoline:

5 g of 2-amino-3-cyano-4-chloro-6- (4-acetylpiperazin-1-yl) quinoline and 15 ml of benzylamine were stirred at 125 ° C for 1 hour. The reaction mixture was then poured onto 30 ml of water, the resulting precipitate was filtered, washed with 20 ml of water and dried, yielding 4 g of the target compound (MH ⁺ : 401).

h) 3-Methoxy-N- [6- (4-acetylpiperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzamide:

To a solution of 1.2 g of 2-amino-3-cyano-4-benzylamino-6- (4-acetylpiperazin-1-yl) quinoline in 20 ml of pyridine was added 1.5 g of 3-methoxybenzoyl chloride and the mixture was heated at the boiling point of the solvent within 5 hours. The reaction mixture was poured onto 30 g of ice water and the precipitated solid was filtered. After drying, 0.45 g of the target compound was obtained (MH ⁺ : 535).

i) 1-amino-2- (3-methoxybenzoylamino) -3-cyano-4-benzylamino-6- (4-acetylpiperazin-1-yl) quinolinium tosylate:

To a solution of 0.72 g of 3-methoxy-N- [6- (4-acetylpiperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzamide in 20 ml of dimethylformamide was added dropwise at 20 ° C over 15 minutes, 0.6 g of O-tosylhydroxylamine in 25 ml of dichloromethane. After 5 hours of stirring, the precipitated crystalline material was filtered. After drying, 0.65 g of the target compound was obtained (MH ⁺ : 551).

j) 2- (3-Methoxyphenyl) -7- (4-acetylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline:

A solution of 0.7 g of 1-amino-2- (3-methoxybenzoylamino) -3-cyano-4-benzylamino-6- (4-acetylpiperazin-1-yl) quinolinium tosylate, 5 ml of pyridine and 0.3 ml of DBU was heated at boiling point of the solvent for 8 hours. The reaction mixture was poured onto 15 ml of water and the precipitated solid was filtered. After drying, 0.15 g of the target compound was obtained (MH ⁺ : 532).

^oneH-NMR (DMSO-d₆), δ, ppm: 8.68 (broad, 1H); 8.33 (d, 1H); 7.89-7.64 (m, 4H); 7.53-7.05 (m, 7H); 5.15 (d, 2H); 3.82 (s, 3H); 3.38-3.35 (m, 4H); 2.63-2.59 (m, 4H); 2.45 (s, 3H).

EXAMPLE 8.2

2- (3-Methoxyphenyl) -7- (4-acetylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hydrosulfate:

The target compound was obtained by the general method described above by adding a solution of sulfuric acid to the compound obtained according to Example 8.

^oneH-NMR (DMSO-d₆), δ, ppm: 8.78 (broad, 1H); 8.38 (d, 1H); 7.91-7.64 (m, 4H); 7.63-7.05 (m, 7H); 5.17 (d, 2H); 3.88 (s, 3H); 3.68-3.45 (m, 4H); 2.63-2.59 (m, 4H); 2.48 (s, 3H).

EXAMPLE 9

2- (3-methoxyphenyl) -7- (piperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline

In the general formula (I), R ¹ and R ² are a hydrogen atom, R ³ is phenyl, R ⁵ is 3-methoxyphenyl, R ⁴ is a group (b) where W is a nitrogen atom, Z is a group —NR ¹² -, where R ¹² is a hydrogen atom, m and o are 2, r, p and t are 0, R ¹³ is a cyano group, X is an NH group, and n is 1.

a) 2- (3-methoxyphenyl) -7- (piperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline:

0.24 g of 2- (3-methoxyphenyl) -7- (4-acetylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline in 8 ml of 3 N. hydrochloric acid solution was heated at the boiling point of the solvent for 6 hours. The reaction mixture was neutralized with a 10% sodium hydroxide solution, and the precipitated solid was filtered. After drying, 0.1 g of the target compound was obtained (MH ⁺ : 490).

¹ H-NMR (DMSO-d ₆ ), δ, ppm: 8.68 (broad s, 1H); 8.33 (d, 1H); 8.11 (br., 1H); 7.89-7.64 (m, 4H); 7.53-7.05 (m, 7H); 5.15 (d, 2H); 3.82 (s, 3H); 3.38-3.35 (m, 4H); 2.63-2.59 (m, 4H).

EXAMPLE 9.2

2- (3-methoxyphenyl) -7- (piperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline maleate:

The target compound was prepared by the general method disclosed above by adding maleic acid solution to the compound obtained according to Example 9.

^oneH-NMR (DMSO-d₆), δ, ppm: 8.68 (broad, 1H); 8.33 (d, 1H); 8.02 (broad. 1H); 7.89-7.64 (m, 4H); 7.53-7.05 (m, 7H); 6.32 (s, 2H); 5.13 (d, 2H); 3.82 (s, 3H); 3.38-3.35 (m, 4H); 2.63-2.59 (m, 4H).

EXAMPLE 10

2-Phenyl-7- (pyridin-3-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline

In the general formula (I), R ¹ and R ² are a hydrogen atom, R ³ is phenyl, R ⁴ is pyridin-3-yl, R ⁵ is phenyl, R ¹³ is a cyano group, X is an NH group, and n = one.

a) 1,2-Diamino-3-cyano-4-hydroxy-6-iodoquinolinium tosylate:

0.62 g of 2-amino-3-cyano-4-hydroxy-6-iodoquinoline was stirred for 40 minutes in 10 ml of dimethylformamide in the presence of 1 g of solid potassium carbonate, then a solution of 0.6 g of O-tosyl-hydroxylamine was added dropwise. in 14 ml of dichloromethane. After stirring the reaction mixture at ambient temperature for 4 hours, the precipitated solid was filtered and dried, yielding 0.57 g of the target compound (MH ⁺ : 327).

b) 2-Phenyl-7-iodine-9-hydroxy-10-cyano-s-triazolo [1,5-a] quinoline:

0.32 g of 1,2-diamino-3-cyano-4-hydroxy-6-iodoquinolinium tosylate was dissolved in 15 ml of ethanol and 2 ml of 1 mol / liter sodium ethoxide in ethanol solution and 0.16 g of benzaldehyde were added to this solution. . The reaction mixture was heated at the boiling point of the solvent for 1 hour. The precipitated crystalline material was filtered and washed with ethanol and water. After drying, 0.34 g of the target compound was obtained (MH ⁺ : 413).

c) 2-Phenyl-7-iodo-9-chloro-10-cyano-s-triazolo [1,5-a] quinoline:

To a solution of 5 g of 2-phenyl-7-iodo-9-hydroxy-10-cyano-s-triazolo [1,5-a] quinoline in 50 ml of acetonitrile, 9 g of phosphoryl chloride was added and the mixture was heated at the boiling point of the solvent for 5 hours . The reaction mixture was poured into 500 ml of ice water, the solid material was filtered and dried, yielding 5 g of the target compound (MH ⁺ : 431).

d) 2-phenyl-7-iodine-9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline:

2.5 g of 2-phenyl-7-iodo-9-chloro-10-cyano-s-triazolo [1,5-a] quinoline and 10 g of benzylamine were mixed and stirred at ambient temperature for 15 minutes. The reaction mixture was diluted with diethyl ether-hexane, and the precipitated solid was filtered. After drying, 1.88 g of the target compound was obtained (MH ⁺ : 562).

e) 2-phenyl-7- (pyridin-3-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline:

To a suspension of 0.6 g of 2-phenyl-7-iodo-9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline in 10 ml of dimethoxyethane was added 0.1 g of tetrakis (triphenylphosphine) palladium (0) 0.25 g of pyridin-3-boronic acid and 10 ml of sodium bicarbonate solution at a concentration of 1 mol / liter. The reaction mixture was stirred under argon atmosphere at the boiling point of the solvent for 5 hours, then it was evaporated and the residue was treated with ethyl acetate. The precipitated solid was filtered. After drying, 0.3 g of the target compound is obtained (MH ⁺ : 453).

The above compound can also be obtained as follows:

f) 2-Phenyl-7-trimethylstannyl-9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline:

A solution of 0.25 g of 2-phenyl-7-iodo-9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline, 0.6 g of hexamethyldistannate and 0.1 g of tetrakis (triphenylphosphine) palladium (0 ) in 3 ml of dioxane was heated at the boiling point of the solvent under nitrogen atmosphere for 5 hours. The solvent was then removed and the residue was treated with diethyl ether. The precipitated solid was filtered. After drying, 0.24 g of the target compound was obtained (M ⁺ : 539).

g) 2-Phenyl-7- (pyridin-3-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline:

To a solution of 0.2 g of 2-phenyl-7-trimethylstannyl-9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline in 10 ml of dimethylformamide was added 0.05 g of tetrakistriphenylpalladium (O) and 0.1 g of 3-bromopyridine. The solution was stirred at 100 ° C. under nitrogen. The solvent was then removed under reduced pressure, and the residue was treated with ethyl acetate. The precipitated solid was filtered. After drying, 0.1 g of the target compound was obtained (MH ⁺ : 453).

^oneH-NMR (DMSO-d₆), δ, ppm: 8.68 (broad, 1H); 8.33 (d, 1H); 8.12-7.91 (m, 4H); 7.89-7.64 (m, 5H); 7.53-7.05 (m, 7H); 5.15 (d, 2H).

EXAMPLE 10.2

2-Phenyl-7- (pyridin-3-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hydrosulfate:

The target compound was obtained by the general method described above by adding a solution of sulfuric acid to the compound obtained according to Example 10.

^oneH-NMR (DMSO-d₆), δ, ppm: 8.78 (broad, 1H); 8.43 (d, 1H); 8.32-7.96 (m, 4H); 7.89-7.74 (m, 5H); 7.53-7.05 (m, 7H); 5.17 (d, 2H).

EXAMPLE 11

2-Phenyl-7- (4-methylpiperazin-1-yl) -9- (2-pyridylmethylamino) -10-cyano-s-triazolo [1,5-a] quinoline

In the general formula (I), R ¹ and R ² are a hydrogen atom, R ³ is pyridin-2-yl, R ⁴ is a group (b) where W is a nitrogen atom, Z is a group —NR ¹² -, where R ¹² is methyl, the values of m and o are 2, the values of r, p and t are 0, R ⁵ is phenyl, R ¹³ is a cyano group, X is an NH group, and n is 1.

a) 1,2-Diamino-3-cyano-4-hydroxy-6- (4-amino-4-methylpiperazin-4-yl-1-yl) quinolinium ditosylate:

To a solution of 3.7 g of 2-amino-3-cyano-4-hydroxy-6- (4-methylpiperazin-1-yl) quinoline in 20 ml of dimethylformamide was added dropwise at 20 ° C. over 15 minutes, 4.4 g of O- tosylhydroxylamine in 50 ml of dichloromethane. After 5 hours of stirring, the precipitated crystalline material was filtered and dried, yielding 3.1 g of the target compound (MH ⁺ : 315).

b) 2-Phenyl-7- (4-methylpiperazin-1-yl) -9-hydroxy-10-cyano-s-triazolo [1,5-a] quinoline:

3.1 g of 1,2-diamino-3-cyano-4-hydroxy-6- (4-amino-4-methylpiperazin-4-yl-1-yl) quinolinium ditosylate was dissolved in 50 ml of ethanol and 20 was added to this solution ml of sodium ethylate at a concentration of 1 mol / liter in ethanol and 2 g of benzaldehyde. The reaction mixture was heated at the boiling point of the solvent for 4 hours. The precipitated crystalline material was filtered and recrystallized from dimethylformamide. After drying, 1.15 g of the target compound was obtained (MH ⁺ : 385).

c) 2-Phenyl-7- (4-methylpiperazin-1-yl) -9-chloro-10-cyano-s-triazolo [1,5-a] quinoline:

A mixture of 1.5 g of 2-phenyl-7- (4-methylpiperazin-1-yl) -9-hydroxy-10-cyano-s-triazolo [1,5-a] quinoline and 3.4 ml of phosphoryl chloride was heated at 120 ° C for 4 hours. The cooled reaction mixture was poured onto 30 g of ice, the mixture was adjusted to a pH of 8, 10% sodium hydroxide solution, and the resulting precipitate was filtered. After drying, 1.3 g of the target compound was obtained (MH ⁺ : 403).

d) 2-phenyl-7- (4-methylpiperazin-1-yl) -9- (2-pyridylmethylamino) -10-cyano-s-triazolo [1,5-a] quinoline:

1 g of 2-phenyl-7- (4-methylpiperazin-1-yl) -9-chloro-10-cyano-s-triazolo [1,5-a] quinoline in 5 ml of 2- (aminomethyl) pyridine was stirred at ambient temperature medium for 2 hours, then the reaction mixture was diluted with 20 ml of water and the precipitated solid was filtered. After drying, 1.1 g of the target compound was obtained (MH ⁺ : 475).

^oneH-NMR (DMSO-d₆), δ, ppm: 8.68 (broad, 1H); 8.33 (d, 1H); 8.19-7.64 (m, 4H); 7.53-7.05 (m, 7H); 5.15 (d, 2H); 3.38-3.35 (m, 4H); 2.63-2.59 (m, 4H); 2.26 (s, 3H).

EXAMPLE 11.2

2-phenyl-7- (4-methylpiperazin-1-yl) -9- (2-pyridylmethylamino) -10-cyano-s-triazolo [1,5-a] quinoline hydrochloride:

The target compound was obtained by the general method described above by adding a hydrochloric acid solution to the compound obtained according to Example 11.

^oneH-NMR (DMSO-d₆), δ, ppm: 8.78 (broad, 1H); 8.43 (d, 1H); 8.29-7.64 (m, 4H); 7.53-7.05 (m, 7H); 5.15 (d, 2H); 3.38-3.35 (m, 4H); 2.73-2.59 (m, 4H); 2.36 (s, 3H).

EXAMPLE 12

2- (3-methoxyphenyl) -7- (pyridin-3-yl) -9- (4-pyridylmethylamino) -10-cyano-s-triazolo [1,5-a] quinoline

In the general formula (I), R ¹ and R ² are a hydrogen atom, R ³ is pyridin-4-yl, R ⁴ is pyridin-3-yl, R ⁵ is 3-methoxyphenyl, R ¹³ is a cyano group, X is a group NH, and n = 1.

a) 1,2-Diamino-3-cyano-4-hydroxy-6-iodo-quinolinium tosylate:

0.62 g of 2-amino-3-cyano-4-hydroxy-6-iodoquinoline in 10 ml of dimethylformamide was stirred with 1 g of solid potassium carbonate for 40 minutes. Then, 0.6 g of O-tosylhydroxylamine in 14 ml of dichloromethane was added dropwise to the reaction mixture. Stirring at ambient temperature was continued for 4 hours. The precipitated crystalline material was filtered and dried, yielding 0.57 g of the target compound (MH ⁺ : 327).

b) 2- (3-Methoxyphenyl) -7-iodo-9-hydroxy-10-cyano-s-triazolo [1,5-a] quinoline:

0.32 g of 1,2-diamino-3-cyano-4-hydroxy-6-iodoquinolinium tosylate obtained in Example 10 was dissolved in 15 ml of ethanol and 2 ml of sodium ethoxide at a concentration of 1 mol / liter in ethanol was added to this solution. solution and 0.16 g of 3-methoxybenzaldehyde. The reaction mixture was heated at the boiling point of the solvent for 1 hour. The precipitated solid was filtered and washed with ethanol and water. After drying, 0.33 g of the target compound is obtained (MH ⁺ : 442).

c) 2- (3-methoxyphenyl) -7-iodo-9-chloro-10-cyano-s-triazolo [1,5-a] quinoline:

To a solution of 5 g of 2- (3-methoxyphenyl) -7-iodo-9-hydroxy-10-cyano-s-triazolo [1,5-a] quinoline in 50 ml of acetonitrile was added 9 g of phosphoryl chloride and the mixture was heated at the boiling point of the solvent within 5 hours. The reaction mixture was poured onto 500 ml of ice water, the precipitate was filtered and dried, yielding 5 g of the target compound (MH ⁺ : 461).

d) 2- (3-Methoxyphenyl) -7-iodo-9- (4-pyridylmethylamino) -10-cyano-s-triazolo [1,5-a] quinoline:

2.5 g of 2- (3-methoxyphenyl) -7-iodo-9-chloro-10-cyano-s-triazolo [1,5-a] quinoline and 10 g of (4-pyridyl) methylamine were mixed and stirred at ambient temperature Wednesday for 15 minutes. The reaction mixture was diluted with diethyl ether / hexane, and the precipitated solid was filtered. After drying, 1.88 g of the target compound was obtained (MH ⁺ : 533).

e.) 2- (3-methoxyphenyl) -7- (pyridin-3-yl) -9- (4-pyridylmethylamino) -10-cyano-s-triazolo [1,5-a] quinoline:

To a suspension of 0.6 g of 2- (3-methoxyphenyl) -7-iodo-9- (4-pyridylmethylamino) -10-cyano-s-triazolo [1,5-a] quinoline in 10 ml of dimethoxyethane was added tetrakistriphenylpalladium (0), 0.25 g of pyridin-3-boronic acid and 10 ml of sodium bicarbonate solution at a concentration of 1 mol / liter. The reaction mixture was stirred under argon atmosphere at the boiling point of the solvent for 5 hours, then it was evaporated and the residue was treated with ethyl acetate. The precipitated solid was filtered. After drying, 0.35 g of the target compound was obtained (MH ⁺ : 484).

^oneH-NMR (DMSO-d₆), δ, ppm: 8.68 (broad, 1H); 8.33 (d, 1H); 8.29-7.84 (m, 4H); 7.79-7.64 (m, 3H); 7.53-7.05 (m, 7H); 5.18 (d, 2H); 3.84 (s, 3H).

EXAMPLE 12.2

2- (3-Methoxyphenyl) -7- (pyridin-3-yl) -9- (4-pyridylmethylamino) -10-cyano-s-triazolo [1,5-a] quinoline hydrosulfate:

The target compound was obtained by the general method described above by adding a solution of sulfuric acid to the compound obtained according to Example 12.

^oneH-NMR (DMSO-d₆), δ, ppm: 8.78 (broad, 1H); 8.38 (d, 1H); 8.36-7.89 (m, 4H); 7.79-7.69 (m, 3H); 7.63-7.05 (m, 7H); 5.18 (d, 2H); 3.91 (s, 3H).

In accordance with the above procedures, using the appropriate starting materials, the following compounds of general formula (I) were obtained, shown in Table 1:

EXAMPLE 39

Known methods were obtained tablets of the following composition:

Active ingredient 25 mg Lactose 50 mg Avicel 21 mg Crospovidone 3 mg Magnesium stearate 1 mg

BIOLOGY

WAYS

Adenosine A Human Receptor Binding ₃

Preparation of a membrane suspension: Cloned Golden Hamster ovary cells expressing the human A ₃ receptor (hereinafter: CHO-hA ₃ ) were cultured accordingly. Upon the merging of the cell layer, the culture fluid was removed from the cells, washing them with PBS at 37 ° C, then the cells were suspended in ice-cold PBS, washed 3 times with PBS, centrifuged (1000 × g 10 minutes) (Sigma 3K30) and homogenized using Teflon homogenizer (B. Braun Potter S) at a rotation speed of 1500 rpm for 15 s in the following buffer: 50 mm Tris, 10 mm MgCl ₂ , 1 mm EDTA, pH 8.0. The homogenate was centrifuged (43,000 g, 10 minutes). The precipitate was suspended in the above buffer, protein concentration 0.1 mg / ml (Bradford method). Aliquots of membrane preparations were maintained at -80 ° C. Alternatively, the membrane preparation hA3-CHO from Perkin Elmer was used.

Binding protocol: incubate the membrane preparation CHO-hA₃ (2 μg protein content) in the presence of the test material and 0.5 nM [¹²⁵I] AB-MECA (4-amino-3-iodine-benzyl-5'-N-methylcarboxamide-adenosine) (100,000 cpm) in incubation buffer (50 mm Tris, 10 mm MgCl₂, 1 mM EDTA, 3 U / ml adenosine deaminase, pH 8.0). The non-specific binding of the labeled ligand in the presence of 100 μM R-PIA (N⁶- [L-2-phenylisopropyl] adenosine). The total reaction volume is 50 μl for 60 minutes at ambient temperature. Filter the reaction mixture through Whatman GF / B fiberglass filters (pre-soaked in 0.5% polyethyleneimine for 3 hours) under a vacuum of 25 Hgmm, washed with 4 × 1 ml of ice-cold wash buffer (50 mM Tris, 10 mM MgCl₂, 1 mM EDTA, pH 8.0), on a 96-well Brandel cell harvester. Radioactivity is detected in a gamma counter (1470 Wizard, Wallac). Inhibition [%] = 100 - ((activity in the presence of the test compound is nonspecific activity) / (total activity is nonspecific activity)) * 100

Adenosine A Human Receptor Binding _one

Binding protocol: incubate the membrane preparation expressing the human adenosine A1 receptor A1 CHO cells (protein content: 10 μg), (source: Perkin-Elmer) in the presence of the test material and 10 nM [ ³ H] DPCPX (8-cyclopentyl-1,3-dipropylxanthine ) (200,000 dpm) in incubation buffer (50 mM Tris HCl, pH 7.4, 3 U / ml adenosine deaminase). Non-specific binding of the labeled ligand was determined in the presence of 10 μM R-PIA (N ⁶ - [L-2-phenylisopropyl] adenosine). Total reaction volume: 100 μl, for 3 hours at ambient temperature. Filter the reaction mixture through Whatman GF / B fiberglass filters (pre-soaked in 0.5% polyethyleneimine for 3 hours) under a vacuum of 25 Hgmm, washed with 4 × 1 ml of ice-cold wash buffer (50 mM Tris HCl, pH 7.4) on 96 well Brandel Cell Harvester. Radioactivity is detected in a beta particle counter (1450 Microbeta, Wallac), in the presence of 200 μl HiSafe-3 cocktail. Inhibition [%] = 100 - ((activity in the presence of the test compound is nonspecific activity) / (full activity is nonspecific activity)) * 100.

Adenosine A Human Receptor Binding _2a

Binding Protocol: Incubate the membrane preparation of HEK-293 cells expressing the human adenosine A _2a receptor (10 μg protein content), (source: Perkin-Elmer, in the presence of test material and 20 nM [ ³ H] CGS-21680 (2- [p - (2-carbonylethyl) phenylethylamino] -5'-N-ethylcarboxamido-adenosine) (200,000 dpm) in incubation buffer (50 mM Tris-HCl, 10 mM MgCl ₂ , 1 mM EDTA, 2 U / ml adenosine deaminase, pH 7.4) Non-specific binding is determined in the presence of 50 μM NECA (5'-N-ethylcarboxamido-adenosine). Total reaction volume: 100 μl for 90 minutes at ambient temperature. filter the reaction mixture under vacuum 25 Hg mm through Whatman GF / B glass fiber filters (pre-soaked in 0.5% polyethyleneimine for 3 hours), wash with 4 × 1 ml ice-cold wash buffer (50 mM Tris HCl, 10 mM MgCl ₂ , 1 mM EDTA, 0.9% NaCl, pH 7.4) on a 96-well Brandel cell harvester Radioactivity is detected in a beta particle counter (1450 Microbeta, Wallac) in the presence of 200 μl HiSafe-3 cocktail. Inhibition [%] = 100 - ((activity in the presence of the test compound is nonspecific activity) / (full activity is nonspecific activity)) * 100.

Adenosine A Human Receptor Binding _2b

Binding Protocol: Incubate the membrane preparation of HEK-293 cells expressing the human adenosine A _2b receptor (10 μg protein content), (source: Perkin-Elmer, in the presence of test material and 32.4 nM [ ³ H] DPCPX (8-cyclopentyl- 1,3-dipropylxanthine) (800,000 dpm) in incubation buffer (50 mM Tris-HCl, 10 mM MgCl ₂ , 1 mM EDTA, 0.1 mM benzamidine, 2 U / ml adenosine deaminase, pH 6.5). Non-specific binding of the labeled ligand in the presence of 100 μM NECA (5'-N-ethylcarboxamido-adenosine). Total reaction volume: 100 μl for 30 minutes at ambient temperature The reaction mixture is filtered under vacuum 25 Hgmm through Whatman GF / B glass fiber filters (pre-soaked in 0.5% polyethyleneimine for 3 hours), washed with 4 × 1 ml ice-cold wash buffer (50 mM Tris-HCl, pH 6 , 5) on a 96-well Brandel cell harvester Radioactivity is detected: in a beta particle counter (1450 Microbeta, Wallac) in the presence of 200 μl HiSafe-3 cocktail. Inhibition [%] = 100 - ((activity in the presence of the test compound is nonspecific activity) / (total activity is nonspecific activity)) * 100.

Mouse model allergy

For experiments, male BalbC mice weighing 20-25 g were used. The animals were first allergic to egg albumin, then, three weeks after the first injection of egg albumin, they were included in the experiment. On the day of the experiment, the mice were treated (by ingestion) with experimental material (or a vehicle not containing any active ingredient), then, after a suitable waiting period, they were anesthetized. After surgical opening of the trachea, 10 microliters of a 1% solution of egg albumin were injected into the trachea.

The control group received the vehicle (physiological saline) into the trachea. After surgical closure of the trachea and treatment, the wounds of the animals were separated and kept under control in their usual living conditions for 24 hours.

After 24 hours, the animals were killed by an overdose of anesthesia, the trachea was opened again and the lung was washed with buffer solution. The buffer solution was centrifuged, the cell pellet was resuspended, and then the cells were counted. The total number of cells was determined and various white blood cells were sorted based on morphology. To determine the effectiveness of the experimental material,% inhibition was calculated compared to the control group. To determine the effect value, a statistical evaluation was performed.

BIOLOGICAL RESULTS:

A compound was considered biologically active if, at a concentration of 1 μM, under the above experimental conditions, it inhibits the binding of the labeled ligand to human A ₃ adenosine receptors with an activity of more than 80%.

Based on the radioisotope saturation curves, a dissociation constant (K_d) labeled ligand [¹²⁵I] AB-MECA on a membrane preparation CHO-hA₃. By value of K_dusing the Cheng-Prusoff equation (Y. J. Cheng and W. H. Prusoff, Biochem. Pharmacol. 22: 3099, 1973) affinity constants (K_i) test compounds were calculated from their IC values_fifty.

The compounds of general formula (I) show an overall IC ₅₀ value of less than 500 nM. Preferred compounds shown in the examples show an IC ₅₀ value of less than 100 nM. The most active compounds of the general formula (I) show an IC ₅₀ value in the range of 1 nM to 20 nM.

The compounds of general formula (I) have good bioavailability and are selective compared to subtypes of human adenosine receptors A ₁ , A _2a and A _2b .

In vivo studies of the compounds of general formula (I) according to the invention showed that they are very active inhibitors of the inflammation processes observed in asthma.

In addition, the duration of action of the compounds of general formula (I) after intravenous and oral administration is long, their ID _50s are low, and their toxicological profiles and side effect profiles are good.

For example, binding values for A ₃ adenosine receptor, solubility, and anti-inflammatory activity of the compounds of general formula (I) described in Examples 1, 17, and 18 are shown in Table 2 as follows.

Table 2. Example IC ₅₀ [nM] Solubility [mg / L] pH: 1; 6.5; 7.5 Inhibition of cell migration [%] * one 38 500; 0.2; 2 81 17 7.7 3000; 0.5; 5 88 eighteen eleven 2500; 0.5; 13 57 * Egg albumin-induced cell migration,% inhibition (complete), orally in mice for 24 hours, 10 mg / kg CMC.

The above data show that the compounds of general formula (I) according to the invention are potentially outstanding therapeutic agents.

Claims (24)

1. Compounds of General Formula (I)

in which R ¹ represents a hydrogen atom or methyl;
R ² represents a hydrogen atom or methyl;
R ³ is phenyl or
6 membered heterocyclic ring containing one nitrogen atom;
R ⁴ is a 6 membered heterocyclic ring containing one nitrogen atom, or
a group of general formula (a),

in which R ⁶ and R ⁷ independently represent C _3-6 cycloalkyl, straight or branched C _1-4 alkyl, or
a group of general formula (b)

in which R ⁸ and R ⁹ independently represent straight or branched C _1-4 alkyl;
Z is an oxygen atom or a group —NR ¹² -, where R ¹² is a hydrogen atom, straight or branched C _1-4 alkyl, C _3-6 cycloalkyl, benzyl, —CH ₂ —acetyl, —CH ₂ —CH ₂ —O— CH ₂ —CH ₃ or acetyl;
W represents a nitrogen atom or a group —CH—;
m is 2;
o is 2;
p is zero or 1;
r is zero or 1;
t is zero;
R ⁵ is phenyl optionally substituted with one or more identical or different, straight or branched C _1-4 alkyl groups, straight or branched C _1-4 alkoxy groups, hydroxyl groups or halogen atoms, or a 5- or 6-membered heterocyclic ring containing one nitrogen atom or one nitrogen atom and one sulfur atom;
R ¹³ represents a cyano group;
X is a group —NH—;
n is 1;
and their pharmaceutically acceptable salts and solvates. 2. The compounds of General formula (I) according to claim 1, in which
R ¹ represents a hydrogen atom;
R ² represents a hydrogen atom;
R ³ is phenyl or
6 membered heterocyclic ring containing one nitrogen atom;
R ⁴ denotes a 6-membered heterocyclic ring containing one nitrogen atom, or a group of General formula (b), in which
R ⁸ and R ⁹ are methyl;
Z is an oxygen atom or a group —NR ¹² -, where R ¹² is a hydrogen atom, methyl, benzyl or acetyl;
W represents a nitrogen atom;
m is 2;
o is 2;
p is zero or 1;
r is zero or 1;
t is zero;
R ⁵ is phenyl, optionally substituted with a methoxy group, a hydroxyl group or a halogen atom, or a 5- or 6-membered heterocyclic ring containing one nitrogen atom, or one nitrogen atom and one sulfur atom;
R ¹³ represents a cyano group;
X is a group —NH—;
n is 1;
and their pharmaceutically acceptable salts and solvates. 3. The following compounds according to claim 1:
2- (3-methoxyphenyl) -7- (morpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline,
2- (4-methoxyphenyl) -7- (morpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline,
2- (4-methoxyphenyl) -7- (2,6-trans-dimethylmorpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline,
2- (pyridin-4-yl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline,
2- (4-methoxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline,
2- (3-methoxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline,
2- (3-hydroxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-3-triazolo [1,5-a] quinoline,
2- (3-methoxyphenyl) -7- (4-acetylpiperazin-1-yl) -9-benzylamino-10-cyano-3-triazolo [1,5-a] quinoline,
2- (3-methoxyphenyl) -7- (piperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline,
2-phenyl-7- (pyridin-3-yl) -9-benzylamino-10-cyano-z-triazolo [1,5-a] quinoline,
2-phenyl-7- (4-methylpiperazin-1-yl) -9- (2-pyridylmethylamino) -10-cyano-s-triazolo [1,5-a] quinoline,
2- (3-methoxyphenyl) -7- (pyridin-3-yl) -9- (4-pyridylmethylamino) -10-cyano-3-triazolo [1,5-a] quinoline,
and their pharmaceutically acceptable salts and solvates. 4. The following compounds according to claim 1:
2- (3-methoxyphenyl) -7- (morpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hydrochloride,
2- (4-methoxyphenyl) -7- (morpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hydrochloride,
2- (4-methoxyphenyl) -7- (2,6-dimethylmorpholin-4-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hydrosulfate,
2- (pyridin-4-yl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline maleate,
2- (4-methoxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hemifumarate monohydrate,
2- (3-methoxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline hemifumarate hemihydrate,
2- (3-hydroxyphenyl) -7- (4-methylpiperazin-1-yl) -9-benzylamino-10-cyano-3-triazolo [1,5-a] quinoline hydrochloride,
2- (3-methoxyphenyl) -7- (4-acetylpiperazin-1-yl) -9-benzylamino-10-cyano-3-triazolo [1,5-a] quinoline hydrosulfate,
2- (3-methoxyphenyl) -7- (piperazin-1-yl) -9-benzylamino-10-cyano-s-triazolo [1,5-a] quinoline maleate,
2-phenyl-7- (pyridin-3-yl) -9-benzylamino-10-cyano-5-triazolo [1,5-a] quinoline hydrosulfate,
2-phenyl-7- (4-methylpiperazin-1-yl) -9- (2-pyridylmethylamino) -10-cyano-s-triazolo [1,5-a] quinoline hydrochloride,
2- (3-methoxyphenyl) -7- (pyridin-3-yl) -9- (4-pyridylmethylamino) -10-cyano-s-triazolo [1,5-a] quinoline hydrosulfate. 5. A method of obtaining compounds of General formula (I) according to claim 1 and their pharmaceutically acceptable salts and solvates, characterized in that for the preparation of compounds of general formula (I), in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , X and n are as defined in claim 1, a 1,2-diaminoazinium salt of the general formula (II)

in which R ¹ , R ² , R ³ , R ⁴ , R ¹³ , X and n are as defined in claim 1, and TsO ^- denotes a p-toluenesulfonate anion,
react with a compound of general formula (IV)

in which the value of R ^{5 is} defined in claim 1 and Y represents a hydrogen atom, a halogen atom or a C _1-4 alkoxy group; and,
if desired, the resulting compound of general formula (I) is converted to its pharmaceutically acceptable salt or solvate. 6. A method for producing compounds of general formula (I) according to claim 1 and their pharmaceutically acceptable salts and solvates, characterized in that for the preparation of compounds of general formula (I) in which R ⁴ is a 6-membered heterocyclic ring bonded via a carbon atom containing one nitrogen atom or a group of the general formula (b) in which W represents a —CH— group and the values Z, m, o, p, r, R ⁸ and R ⁹ are as defined in claim 1, and the values of R ¹ R ² , R ³ , R ⁵ , R ¹³ , X and n are as defined in claim 1,
the triazole derivative of the general formula (V) is introduced into the reaction

in which E represents a halogen atom or trifluoromethanesulfonyl, and the values of R ¹ , R ² , R ³ , R ⁵ , R ¹³ , X and n are as defined in claim 1,
and a compound of general formula (VII)

in which the value of R ⁴ is as defined above;
and, if desired, the resulting compound of general formula (I) is converted to a pharmaceutically acceptable salt or solvate thereof. 7. A method for producing compounds of general formula (I) according to claim 1, and their pharmaceutically acceptable salts and solvates, characterized in that for the preparation of compounds of general formula (I) in which R ⁴ is a 6-membered heterocyclic ring bonded through an atom a carbon containing one nitrogen atom or a group of the general formula (b) in which W represents a —CH— group and the values Z, m, o, p, r, R ⁸ and R ⁹ are as defined in claim 1, and the values of R ¹ , R ² , R ³ , R ⁵ , R ¹³ , X and n are as defined in claim 1,
the trialkyltin triazole derivative of the general formula (VI) is introduced into the reaction

in which R ¹⁴ denotes a straight or branched C _1-4 alkyl, and the values of R ¹ , R ² , R ³ R ⁵ R ¹³ , X and n are as defined in claim 1,
and a compound of general formula (VIII)

in which E represents a halogen atom or trifluoromethanesulfonyl and the value of R ⁴ is as defined above;
and, if desired, the resulting compound of general formula (I) is converted to a pharmaceutically acceptable salt or solvate thereof. 8. A method of obtaining compounds of General formula (I) according to claim 1 and their pharmaceutically acceptable salts and solvates, characterized in that for the preparation of compounds of General formula (I), where the values of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , X and n are as defined in claim 1, a triazole derivative of the general formula (XII) is introduced into the reaction

in which the values of R ⁴ , R ⁵ and R ¹³ are as defined in claim 1,
and a compound of general formula (XIII)

in which the values of X, R ¹ , R ² and R ³ and n are as defined in claim 1;
and, if desired, the resulting compound of general formula (I) is converted to a pharmaceutically acceptable salt or solvate thereof. 9. A method of obtaining compounds of General formula (I) according to claim 1 and their pharmaceutically acceptable salts and solvates, characterized in that for the preparation of compounds of general formula (I), where the values of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , X and n are as defined in claim 1, a compound of general formula (XV)

where the values of X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ and n are as defined in claim 1, TsO ^- is a p-toluenesulfonate anion, cyclized in the presence of an organic or inorganic base and, if desired, the resulting compound of general formula (I) is converted to its pharmaceutically acceptable salt or solvate. 10. A pharmaceutical composition for the treatment of diseases in the development of which the adenosine A ₃ receptor plays a role, characterized in that it contains one or more compounds of the general formula (I), where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , X and n are as defined in claim 1, and / or a pharmaceutically acceptable salt or solvate thereof and one or more excipients used in the pharmaceutical industry. 11. The pharmaceutical composition of claim 10, characterized in that it contains one or more compounds of claim 3 or 4. 12. The compounds of General formula (I), where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , X and n are as defined in claim 1, and their pharmaceutically acceptable salts and solvates for use in treatment of diseases in the development of which the adenosine A ₃ receptor plays a role. 13. The compounds of General formula (I), where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , X and n are as defined in claim 1, and their pharmaceutically acceptable salts and solvates for use according to Claim 12 as adenosine A ₃ receptor ligands for the treatment of dysfunctions of the heart, eyes, kidneys, respiratory system, gastrointestinal tract, joints and central nervous system, for inhibiting mast cell degranulation, for inhibiting cytokine production, and for reducing intraocular pressure, to inhibit the release of TNFα, to prevent migration and activation and eosinophilic and neutrophilic granulocytes and other inflammatory cells, to inhibit smooth muscle contraction of the respiratory tract and to prevent blood plasma infiltration through a blood vessel and inhibition of increased mucin production. 14. Compounds of General formula (I), where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , X and n are as defined in claim 1, and their pharmaceutically acceptable salts and solvates for use according to any of paragraphs 12, 13, as antagonists of the adenosine A ₃ receptor, as an active pharmaceutical ingredient in an anti-asthma, anti-ischemic agent, antidepressant, antiarrhythmic, anti-rheumatic agent, anti-glaucoma, anti-inflammatory agent in inflammatory and irritable bowel diseases, anti-CORD, for for renal function shields, a tumor prevention agent, an antiparkinsonian drug or a medicament for stimulating cognitive function and in the treatment or prevention of the following diseases: cardiac muscle damage during reperfusion, acute respiratory distress syndrome, chronic obstructive pulmonary disease, including chronic bronchitis, pulmonary emphysema or shortness of breath, allergic reactions, including rhinitis, reactions induced by poison ivy, urticaria, scleroderma, arthritis, other autoimmune diseases, inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, irritable bowel syndrome, Addison's disease, psoriasis, joint diseases, hypertension, pathological neurological functions, glaucoma and diabetes. 15. The compounds of General formula (I), where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , X and n are as defined in claim 1, and their pharmaceutically acceptable salts and solvates for use according to any one of claims 12-14 in the treatment of diseases such as asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, glaucoma, tumor, inflammatory bowel disease, irritable bowel syndrome, allergic and inflammatory pain, rheumatoid arthritis, ischemia, hypoxia, heart arrhythmia, kidney disease, and mood-related diseases. 16. The use of compounds of General formula (I), where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , X and n have the meanings defined in claim 1, and / or their pharmaceutically acceptable salts and solvates to obtain a drug suitable for use in the treatment of diseases in the development of which the A ₃ receptor plays a role. 17. The use of the compounds of General formula (I), where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , X and n are as defined in claim 1, and / or their pharmaceutically acceptable salts and solvates according to clause 16, for the manufacture of a medicament for the treatment of diseases such as asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, glaucoma, tumor, inflammatory bowel disease, irritable bowel syndrome, allergic and inflammatory pain, rheumatoid arthritis, ischemia, hypoxia , cardiac arrhythmia, kidney disease and illness Nia associated with mood. 18. A method of treating or preventing the development of a disease in a patient in which the A ₃ receptor plays a role, comprising administering to said patient a pharmaceutically effective amount of one or more compounds of general formula (I), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , X and n are as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof. 19. The method of claim 18, wherein the disease is asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, glaucoma, tumor, inflammatory bowel disease, irritable bowel syndrome, allergic and inflammatory pain, rheumatoid arthritis, ischemia, hypoxia, arrhythmia heart disease, kidney disease, and mood related diseases. 20. Compounds of General Formula (II)

in which the values of R ¹ , R ² , R ¹³ , X and n are as defined in claim 1, R ³ is phenyl, R ⁴ is a 6-membered heterocyclyl containing one nitrogen atom and one oxygen atom as heteroatoms and optionally substituted with two C _1-4 alkyl groups, and TsO ^- denotes the p-toluenesulfonate anion. 21. Compounds of General Formula (VI)

wherein R ¹⁴ is straight or branched C _1-4 alkyl, the values of R ¹ , R ² , R ¹³ , X and n are as defined in claim 1, and R ³ and R ⁵ are phenyl. 22. Compounds of General Formula (XI)

in which the values of R ¹³ are as defined in claim 1, R ⁴ is a 6-membered heterocyclyl containing two nitrogen atoms as heteroatoms and substituted with C _1-4 alkyl, and R ⁵ is phenyl. 23. Compounds of General Formula (XII)

where the values of R ¹³ are as defined in claim 1, R ⁴ is a 6-membered heterocyclyl containing two nitrogen atoms as heteroatoms and substituted with C _1-4 alkyl, and R ⁵ is phenyl. 24. Compounds of General Formula (XV)

in which the values of X, R ¹ , R ² , R ¹³ and n are as defined in claim 1, R ³ is phenyl, R ⁴ is a 6-membered heterocyclyl containing two nitrogen atoms as heteroatoms and substituted by C _{1- 4 by} acyl, R ⁵ is phenyl substituted with C _1-4 alkoxy, and TsO ^- is a p-toluenesulfonate anion.

Images